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1. Application of Machine Learning Prediction of Individual SARS-CoV-2 Vaccination and Infection Status to the French Serosurveillance Survey From March 2020 to 2022: Cross-Sectional Study

Author: Stéphanie Bougeard, Adeline Huneau-Salaun, Mikael Attia, Jean-Baptiste Richard, Caroline Demeret, Johnny Platon, Virginie Allain, Stéphane Le Vu, Sophie Goyard, Véronique Gillon, Sibylle Bernard-Stoecklin, Bernadette Crescenzo-Chaigne, Gabrielle Jones, Nicolas Rose, Sylvie van der Werf, Olivier Lantz, Thierry Rose, and Harold Noël
Subjects: Public aspects of medicine, RA1-1270
Abstract: BackgroundThe seroprevalence of SARS-CoV-2 infection in the French population was estimated with a representative, repeated cross-sectional survey based on residual sera from routine blood testing. These data contained no information on infection or vaccination status, thus limiting the ability to detail changes observed in the immunity level of the population over time. ObjectiveOur aim is to predict the infected or vaccinated status of individuals in the French serosurveillance survey based only on the results of serological assays. Reference data on longitudinal serological profiles of seronegative, infected, and vaccinated individuals from another French cohort were used to build the predictive model. MethodsA model of individual vaccination or infection status with respect to SARS-CoV-2 obtained from a machine learning procedure was proposed based on 3 complementary serological assays. This model was applied to the French nationwide serosurveillance survey from March 2020 to March 2022 to estimate the proportions of the population that were negative, infected, vaccinated, or infected and vaccinated. ResultsFrom February 2021 to March 2022, the estimated percentage of infected and unvaccinated individuals in France increased from 7.5% to 16.8%. During this period, the estimated percentage increased from 3.6% to 45.2% for vaccinated and uninfected individuals and from 2.1% to 29.1% for vaccinated and infected individuals. The decrease in the seronegative population can be largely attributed to vaccination. ConclusionsCombining results from the serosurveillance survey with more complete data from another longitudinal cohort completes the information retrieved from serosurveillance while keeping its protocol simple and easy to implement.
Published: 2023
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2. Prevalence of SARS-CoV-2 antibodies in France: results from nationwide serological surveillance

Author: Stéphane Le Vu, Gabrielle Jones, François Anna, Thierry Rose, Jean-Baptiste Richard, Sibylle Bernard-Stoecklin, Sophie Goyard, Caroline Demeret, Olivier Helynck, Nicolas Escriou, Marion Gransagne, Stéphane Petres, Corinne Robin, Virgile Monnet, Louise Perrin de Facci, Marie-Noelle Ungeheuer, Lucie Léon, Yvonnick Guillois, Laurent Filleul, Pierre Charneau, Daniel Lévy-Bruhl, Sylvie van der Werf, and Harold Noel
Subjects: Science
Abstract: The percentage of national populations infected during the first stages of the COVID-19 pandemic are unclear owing to limited early testing. Here the authors provide a nation-wide prevalence study of SARS-CoV-2 antibodies in France from the first wave of COVID-19 in 2020, including stratification based on age, sex and region.
Published: 2021
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3. C910 chemical compound inhibits the traffiking of several bacterial AB toxins with cross-protection against influenza virus

Author: Yu Wu, Nassim Mahtal, Eléa Paillares, Léa Swistak, Sara Sagadiev, Mridu Acharya, Caroline Demeret, Sylvie Van Der Werf, Florence Guivel-Benhassine, Olivier Schwartz, Serena Petracchini, Amel Mettouchi, Lucie Caramelle, Pierre Couvineau, Robert Thai, Peggy Barbe, Mathilde Keck, Priscille Brodin, Arnaud Machelart, Valentin Sencio, François Trottein, Martin Sachse, Gaëtan Chicanne, Bernard Payrastre, Florian Ville, Victor Kreis, Michel-Robert Popoff, Ludger Johannes, Jean-Christophe Cintrat, Julien Barbier, Daniel Gillet, and Emmanuel Lemichez
Subjects: Biological sciences, Microbiology, Science
Abstract: Summary: The development of anti-infectives against a large range of AB-like toxin-producing bacteria includes the identification of compounds disrupting toxin transport through both the endolysosomal and retrograde pathways. Here, we performed a high-throughput screening of compounds blocking Rac1 proteasomal degradation triggered by the Cytotoxic Necrotizing Factor-1 (CNF1) toxin, which was followed by orthogonal screens against two toxins that hijack the endolysosomal (diphtheria toxin) or retrograde (Shiga-like toxin 1) pathways to intoxicate cells. This led to the identification of the molecule C910 that induces the enlargement of EEA1-positive early endosomes associated with sorting defects of CNF1 and Shiga toxins to their trafficking pathways. C910 protects cells against eight bacterial AB toxins and the CNF1-mediated pathogenic Escherichia coli invasion. Interestingly, C910 reduces influenza A H1N1 and SARS-CoV-2 viral infection in vitro. Moreover, parenteral administration of C910 to mice resulted in its accumulation in lung tissues and a reduction in lethal influenza infection.
Published: 2022
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4. A Comprehensive, Flexible Collection of SARS-CoV-2 Coding Regions

Author: Dae-Kyum Kim, Jennifer J. Knapp, Da Kuang, Aditya Chawla, Patricia Cassonnet, Hunsang Lee, Dayag Sheykhkarimli, Payman Samavarchi-Tehrani, Hala Abdouni, Ashyad Rayhan, Roujia Li, Oxana Pogoutse, Étienne Coyaud, Sylvie van der Werf, Caroline Demeret, Anne-Claude Gingras, Mikko Taipale, Brian Raught, Yves Jacob, and Frederick P. Roth
Subjects: sars-cov-2, coding sequence collection, gateway-compatible, tev (tobacco etch virus) sequence, Genetics, QH426-470
Abstract: The world is facing a global pandemic of COVID-19 caused by the SARS-CoV-2 coronavirus. Here we describe a collection of codon-optimized coding sequences for SARS-CoV-2 cloned into Gateway-compatible entry vectors, which enable rapid transfer into a variety of expression and tagging vectors. The collection is freely available. We hope that widespread availability of this SARS-CoV-2 resource will enable many subsequent molecular studies to better understand the viral life cycle and how to block it.
Published: 2020
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5. Nasopharyngeal and serological anti SARS-CoV-2 IgG/IgA responses in COVID-19 patients

Author: Bernadette Crescenzo-Chaigne, Sylvie Behillil, Vincent Enouf, Nicolas Escriou, Stephane Petres, Marie Noelle Ungeheuer, Jade Ghosn, Sarah Tubiana, Lila Bouadma, Sylvie van der Werf, and Caroline Demeret
Subjects: SARS CoV, Mucosal Immunity, Serology, Infectious and parasitic diseases, RC109-216
Abstract: Background: The systemic antibody responses to SARS-CoV-2 in COVID-19 patients has been extensively studied. However, less is known about the mucosal responses in the upper airways, the site of initial SARS-CoV-2 replication. Methods: The IgG and IgA antibody responses were analysed in plasma and nasopharyngeal swabs from the first four confirmed COVID-19 patients in France. Two were pauci-symptomatic while two developed severe disease. We characterized their antibody profiles by using an in-house ELISA to detect antibodies directed against SARS-CoV-2 Nucleoprotein and Spike. Results: Anti-N IgG and IgA antibodies were detected in the NPS of severe patients only. The levels of antibodies in the plasma markedly differed amongst the patients. The most distinctive features are a strong anti-N IgG response in the severe patient who recovered, and a high anti-N IgA response specifically detected in the fatal case of COVID-19. Conclusions: Anti-N IgG and IgA antibodies are detected in NPS only for severe patients, with levels related to serological antibodies. The severe patients showed different antibody profiles in the plasma, notably regarding the IgA and IgG response to the N antigen, that may reflect different disease outcome. By contrast, pauci-symptomatic patients did not exhibit any mucosal antibodies in NSP, which is associated with a low or absent serological response against both N and S.
Published: 2021
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6. Maximizing binary interactome mapping with a minimal number of assays

Author: Soon Gang Choi, Julien Olivet, Patricia Cassonnet, Pierre-Olivier Vidalain, Katja Luck, Luke Lambourne, Kerstin Spirohn, Irma Lemmens, Mélanie Dos Santos, Caroline Demeret, Louis Jones, Sudharshan Rangarajan, Wenting Bian, Eloi P. Coutant, Yves L. Janin, Sylvie van der Werf, Philipp Trepte, Erich E. Wanker, Javier De Las Rivas, Jan Tavernier, Jean-Claude Twizere, Tong Hao, David E. Hill, Marc Vidal, Michael A. Calderwood, and Yves Jacob
Subjects: Science
Abstract: Comprehensive mapping of binary protein-protein interactions requires to combine several complementary assays. Here, the authors show that complete coverage could be reached with a minimal number of assays as long as they explore various experimental conditions.
Published: 2019
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7. Humoral immunity to SARS-CoV-2 and seasonal coronaviruses in children and adults in north-eastern France

Author: Tom Woudenberg, Stéphane Pelleau, François Anna, Mikael Attia, Françoise Donnadieu, Alain Gravet, Caroline Lohmann, Hélène Seraphin, Raphaël Guiheneuf, Catherine Delamare, Karl Stefic, Julien Marlet, Etienne Brochot, Sandrine Castelain, Olivier Augereau, Jean Sibilia, François Dubos, Damia Meddour, Christèle Gras-Le Guen, Marianne Coste-Burel, Berthe-Marie Imbert-Marcille, Anne Chauvire-Drouard, Cyril Schweitzer, Amélie Gatin, Sandra Lomazzi, Aline Joulié, Hervé HAAS, Aymeric Cantais, Frederique Bertholon, Marie-France Chinazzo-Vigouroux, Mohamed SI Abdallah, Laurence Arowas, Pierre Charneau, Bruno Hoen, Caroline Demeret, Sylvie Van Der Werf, Arnaud Fontanet, and Michael White
Subjects: SARS-CoV-2, COVID-19, seroprevalence, sero-epidemiology, seasonal coronaviruses, antibody response, Medicine, Medicine (General), R5-920
Abstract: Background: Children are underrepresented in the COVID-19 pandemic and often experience milder disease than adolescents and adults. Reduced severity is possibly due to recent and more frequent seasonal human coronaviruses (HCoV) infections. We assessed the seroprevalence of SARS-CoV-2 and seasonal HCoV specific antibodies in a large cohort in north-eastern France. Methods: In this cross-sectional seroprevalence study, serum samples were collected from children and adults requiring hospital admission for non-COVID-19 between February and August 2020. Antibody responses to SARS-CoV-2 and seasonal HCoV (229E, HKU1, NL63, OC43) were assessed using a bead-based multiplex assay, Luciferase-Linked ImmunoSorbent Assay, and a pseudotype neutralisation assay. Findings: In 2,408 individuals, seroprevalence of SARS-CoV-2-specific antibodies was 7-8% with three different immunoassays. Antibody levels to seasonal HCoV increased substantially up to the age of 10. Antibody responses in SARS-CoV-2 seropositive individuals were lowest in adults 18-30 years. In SARS-CoV-2 seronegative individuals, we observed cross-reactivity between antibodies to the four HCoV and SARS-CoV-2 Spike. In contrast to other antibodies to SARS-CoV-2, specific antibodies to sub-unit 2 of Spike (S2) in seronegative samples were highest in children. Upon infection with SARS-CoV-2, antibody levels to Spike of betacoronavirus OC43 increased across the whole age spectrum. No SARS-CoV-2 seropositive individuals with low levels of antibodies to seasonal HCoV were observed. Interpretation: Our findings underline significant cross-reactivity between antibodies to SARS-CoV-2 and seasonal HCoV, but provide no significant evidence for cross-protective immunity to SARS-CoV-2 infection due to a recent seasonal HCoV infection. In particular, across all age groups we did not observe SARS-CoV-2 infected individuals with low levels of antibodies to seasonal HCoV. Funding: This work was supported by the « URGENCE COVID-19 » fundraising campaign of Institut Pasteur, by the French Government's Investissement d'Avenir program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (Grant No. ANR-10-LABX-62-IBEID), and by the REACTing (Research & Action Emerging Infectious Diseases), and by the RECOVER project funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No. 101003589, and by a grant from LabEx IBEID (ANR-10-LABX-62-IBEID).
Published: 2021
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8. Characterization of SARS-CoV-2 Evasion: Interferon Pathway and Therapeutic Options

Author: Mariem Znaidia, Caroline Demeret, Sylvie van der Werf, and Anastassia V. Komarova
Subjects: SARS-CoV-2, innate immunity, virus–host interactions, antagonism, interferon, therapy, Microbiology, QR1-502
Abstract: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. SARS-CoV-2 is characterized by an important capacity to circumvent the innate immune response. The early interferon (IFN) response is necessary to establish a robust antiviral state. However, this response is weak and delayed in COVID-19 patients, along with massive pro-inflammatory cytokine production. This dysregulated innate immune response contributes to pathogenicity and in some individuals leads to a critical state. Characterizing the interplay between viral factors and host innate immunity is crucial to better understand how to manage the disease. Moreover, the constant emergence of new SARS-CoV-2 variants challenges the efficacy of existing vaccines. Thus, to control this virus and readjust the antiviral therapy currently used to treat COVID-19, studies should constantly be re-evaluated to further decipher the mechanisms leading to SARS-CoV-2 pathogenesis. Regarding the role of the IFN response in SARS-CoV-2 infection, in this review we summarize the mechanisms by which SARS-CoV-2 evades innate immune recognition. More specifically, we explain how this virus inhibits IFN signaling pathways (IFN-I/IFN-III) and controls interferon-stimulated gene (ISG) expression. We also discuss the development and use of IFNs and potential drugs controlling the innate immune response to SARS-CoV-2, helping to clear the infection.
Published: 2022
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9. Nonproteolytic K29-Linked Ubiquitination of the PB2 Replication Protein of Influenza A Viruses by Proviral Cullin 4-Based E3 Ligases

Author: Marwah Karim, Elise Biquand, Marion Declercq, Yves Jacob, Sylvie van der Werf, and Caroline Demeret
Subjects: K29-linked ubiquitination, PB2 replication protein, cullin-based E3 ligases, influenza virus, nonproteolytic ubiquitination, post-translational modification, Microbiology, QR1-502
Abstract: ABSTRACT The multifunctional nature of viral proteins is essentially driven by posttranslational modifications (PTMs) and is key for the successful outcome of infection. For influenza A viruses (IAVs), a composite pattern of PTMs regulates the activity of viral proteins. However, almost none are known that target the PB2 replication protein, except for inducing its degradation. We show here that PB2 undergoes a nonproteolytic ubiquitination during infection. We identified E3 ubiquitin ligases catalyzing this ubiquitination as two multicomponent RING-E3 ligases based on cullin 4 (CRL4s), which are both contributing to the levels of ubiquitinated forms of PB2 in infected cells. The CRL4 E3 ligase activity is required for the normal progression of the viral cycle and for maximal virion production, indicating that the CRL4s mediate a ubiquitin signaling that promotes infection. The CRL4s are recruiting PB2 through an unconventional bimodal interaction with both the DDB1 adaptor and DCAF substrate receptors. While able to bind to PB2 when engaged in the viral polymerase complex, the CRL4 factors do not alter transcription and replication of the viral segments during infection. CRL4 ligases catalyze different patterns of lysine ubiquitination on PB2. Recombinant viruses mutated in the targeted lysines showed attenuated viral production, suggesting that CRL4-mediated ubiquitination of PB2 contributes to IAV infection. We identified K29-linked ubiquitin chains as main components of the nonproteolytic PB2 ubiquitination mediated by the CRL4s, providing the first example of the role of this atypical ubiquitin linkage in the regulation of a viral infection. IMPORTANCE Successful infection by influenza A virus, a pathogen of major public health importance, involves fine regulation of the multiple functions of the viral proteins, which often relies on post-translational modifications (PTMs). The PB2 protein of influenza A viruses is essential for viral replication and a key determinant of host range. While PTMs of PB2 inducing its degradation have been identified, here we show that PB2 undergoes a regulating PTM signaling detected during infection, based on an atypical K29-linked ubiquitination and mediated by two multicomponent E3 ubiquitin ligases. Recombinant viruses impaired for CRL4-mediated ubiquitination are attenuated, indicating that ubiquitination of PB2 is necessary for an optimal influenza A virus infection. The CRL4 E3 ligases are required for normal viral cycle progression and for maximal virion production. Consequently, they represent potential candidate host factors for antiviral targets.
Published: 2020
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10. OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1

Author: Akhee Sabiha Jahan, Elise Biquand, Raquel Muñoz-Moreno, Agathe Le Quang, Chris Ka-Pun Mok, Ho Him Wong, Qi Wen Teo, Sophie A. Valkenburg, Alex W.H. Chin, Leo Lit Man Poon, Artejan te Velthuis, Adolfo García-Sastre, Caroline Demeret, and Sumana Sanyal
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Deubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, systematic analyses of DUBs that regulate this pathway have not been performed. Using a ubiquitin C-terminal electrophile, we profile DUBs that function during influenza A virus (IAV) infection and isolate OTUB1 as a key regulator of RIG-I-dependent antiviral responses. Upon infection, OTUB1 relocalizes from the nucleus to mitochondrial membranes together with RIG-I, viral PB2, and NS1. Its expression depends on competing effects of interferon stimulation and IAV-triggered degradation. OTUB1 activates RIG-I via a dual mechanism of K48 polyubiquitin hydrolysis and formation of an E2-repressive complex with UBCH5c. We reconstitute this mechanism in a cell-free system comprising [35S]IRF3, purified RIG-I, mitochondrial membranes, and cytosol expressing OTUB1 variants. A range of IAV NS1 proteins trigger proteasomal degradation of OTUB1, antagonizing the RIG-I signaling cascade and antiviral responses. : Jahan et al. describe the role of Otub1, a deubiquitylase that is induced during virus infection in an interferon-dependent manner to regulate optimal signaling via the RIG-I pathway. Influenza A virus NS1 is able to bind and degrade newly synthesized Otub1 as a means to evade the innate immune response. Keywords: deubiquitylases, RIG-I signaling, ubiquitylation, innate immune response, RNA virus, influenza A, viral subversion strategies
Published: 2020
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11. MARCH8 Ubiquitinates the Hepatitis C Virus Nonstructural 2 Protein and Mediates Viral Envelopment

Author: Sathish Kumar, Rina Barouch-Bentov, Fei Xiao, Stanford Schor, Szuyuan Pu, Elise Biquand, Albert Lu, Brett D. Lindenbach, Yves Jacob, Caroline Demeret, and Shirit Einav
Subjects: Biology (General), QH301-705.5
Abstract: Summary: The mechanisms that regulate envelopment of HCV and other viruses that bud intracellularly and/or lack late-domain motifs are largely unknown. We reported that K63 polyubiquitination of the HCV nonstructural (NS) 2 protein mediates HRS (ESCRT-0 component) binding and envelopment. Nevertheless, the ubiquitin signaling that governs NS2 ubiquitination remained unknown. Here, we map the NS2 interactome with the ubiquitin proteasome system (UPS) via mammalian cell-based screens. NS2 interacts with E3 ligases, deubiquitinases, and ligase regulators, some of which are candidate proviral or antiviral factors. MARCH8, a RING-finger E3 ligase, catalyzes K63-linked NS2 polyubiquitination in vitro and in HCV-infected cells. MARCH8 is required for infection with HCV, dengue, and Zika viruses and specifically mediates HCV envelopment. Our data reveal regulation of HCV envelopment via ubiquitin signaling and both a viral protein substrate and a ubiquitin K63-linkage of the understudied MARCH8, with potential implications for cell biology, virology, and host-targeted antiviral design. : The mechanisms that regulate intracellular viral envelopment are unknown. Kumar et al. report that MARCH8 catalyzes K63-linked polyubiquitination of the HCV nonstructural 2 protein and subsequently ESCRT recruitment and HCV envelopment. MARCH8 is required for infection with other Flaviviridae family members, thereby representing a potential host target for antiviral strategies. Keywords: ubiquitination, hepatitis C virus, HCV, MARCH8, virus-host interactions, proteomics, assembly, envelopment, intracellular membrane trafficking, ESCRT
Published: 2019
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12. Comparative Profiling of Ubiquitin Proteasome System Interplay with Influenza A Virus PB2 Polymerase Protein Recapitulating Virus Evolution in Humans

Author: Elise Biquand, Juline Poirson, Marwah Karim, Marion Declercq, Nicolas Malausse, Patricia Cassonnet, Cyril Barbezange, Marie-Laure Straub, Louis Jones, Sandie Munier, Nadia Naffakh, Sylvie van der Werf, Yves Jacob, Murielle Masson, and Caroline Demeret
Subjects: comparative interactomics, influenza viruses, ubiquitination, virus-host interactions, Microbiology, QR1-502
Abstract: ABSTRACT The optimized exploitation of cell resources is one cornerstone of a successful infection. Differential mapping of host-pathogen protein-protein interactions (PPIs) on the basis of comparative interactomics of multiple strains is an effective strategy to highlight correlations between host proteome hijacking and biological or pathogenic traits. Here, we developed an interactomic pipeline to deliver high-confidence comparative maps of PPIs between a given pathogen and the human ubiquitin proteasome system (UPS). This subarray of the human proteome represents a range of essential cellular functions and promiscuous targets for many viruses. The screening pipeline was applied to the influenza A virus (IAV) PB2 polymerase proteins of five strains representing different levels of virulence in humans. An extensive PB2-UPS interplay has been detected that recapitulates the evolution of IAVs in humans. Functional validation with several IAV strains, including the seasonal H1N1pdm09 and H3N2 viruses, confirmed the biological relevance of most identified UPS factors and revealed strain-independent and strain-specific effects of UPS factor invalidation on IAV infection. This strategy is applicable to proteins from any other virus or pathogen, providing a valuable resource with which to explore the UPS-pathogen interplay and its relationship with pathogenicity. IMPORTANCE Influenza A viruses (IAVs) are responsible for mild-to-severe seasonal respiratory illness of public health concern worldwide, and the risk of avian strain outbreaks in humans is a constant threat. Elucidating the requisites of IAV adaptation to humans is thus of prime importance. In this study, we explored how PB2 replication proteins of IAV strains with different levels of virulence in humans hijack a major protein modification pathway of the human host cell, the ubiquitin proteasome system (UPS). We found that the PB2 protein engages in an extended interplay with the UPS that evolved along with the virus’s adaptation to humans. This suggests that UPS hijacking underlies the efficient infection of humans and can be used as an indicator for evaluation of the potential of avian IAVs to infect humans. Several UPS factors were found to be necessary for infection with circulating IAV strains, pointing to potential targets for therapeutic approaches.
Published: 2017
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13. Recruitment of RED-SMU1 complex by Influenza A Virus RNA polymerase to control Viral mRNA splicing.

Author: Guillaume Fournier, Chiayn Chiang, Sandie Munier, Andru Tomoiu, Caroline Demeret, Pierre-Olivier Vidalain, Yves Jacob, and Nadia Naffakh
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Influenza A viruses are major pathogens in humans and in animals, whose genome consists of eight single-stranded RNA segments of negative polarity. Viral mRNAs are synthesized by the viral RNA-dependent RNA polymerase in the nucleus of infected cells, in close association with the cellular transcriptional machinery. Two proteins essential for viral multiplication, the exportin NS2/NEP and the ion channel protein M2, are produced by splicing of the NS1 and M1 mRNAs, respectively. Here we identify two human spliceosomal factors, RED and SMU1, that control the expression of NS2/NEP and are required for efficient viral multiplication. We provide several lines of evidence that in infected cells, the hetero-trimeric viral polymerase recruits a complex formed by RED and SMU1 through interaction with its PB2 and PB1 subunits. We demonstrate that the splicing of the NS1 viral mRNA is specifically affected in cells depleted of RED or SMU1, leading to a decreased production of the spliced mRNA species NS2, and to a reduced NS2/NS1 protein ratio. In agreement with the exportin function of NS2, these defects impair the transport of newly synthesized viral ribonucleoproteins from the nucleus to the cytoplasm, and strongly reduce the production of infectious influenza virions. Overall, our results unravel a new mechanism of viral subversion of the cellular splicing machinery, by establishing that the human splicing factors RED and SMU1 act jointly as key regulators of influenza virus gene expression. In addition, our data point to a central role of the viral RNA polymerase in coupling transcription and alternative splicing of the viral mRNAs.
Published: 2014
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14. CCHCR1 interacts specifically with the E2 protein of human papillomavirus type 16 on a surface overlapping BRD4 binding.

Author: Mandy Muller and Caroline Demeret
Subjects: Medicine, Science
Abstract: The Human Papillomavirus E2 proteins are key regulators of the viral life cycle, whose functions are commonly mediated through protein-protein interactions with the host cell proteome. We identified an interaction between E2 and a cellular protein called CCHCR1, which proved highly specific for the HPV16 genotype, the most prevalent in HPV-associated cancers. Further characterization of the interaction revealed that CCHCR1 binds the N-terminal alpha helices of HPV16 E2 N-terminal domain. On this domain, the CCHCR1 binding interface overlaps that of BRD4, a key mediator of E2 transcriptional activity. Consequently a physical competition occurs between the two proteins for the binding to HPV16 E2, and CCHCR1 interferes with BRD4-mediated enhancement of E2-dependent transcription. In addition, we showed that the interaction with CCHCR1 induced a massive redistribution of HPV16 E2, from a predominantly nuclear to a cytoplasmic localization in dot-like structures, where E2 perfectly co-localizes with CCHCR1. Such a cytoplasmic docking likely interferes with the nuclear functions of HPV16 E2. Upon co-expression of BRD4 and CCHCR1, E2 accumulates both in the nucleus and in the cytoplasm, indicating that for HPV16, both sub-cellular localization and transcriptional functions of E2 may depend on the proportion of both factors within the cell. We provided evidence of a strong induction of the keratinocyte differentiation marker K10 by HPV16 E2, and showed that this activation is compromised by the interaction with CCHCR1. The specific interaction described here could thus impact on the pathogenesis of HPV16. We propose that it could underlie some specific traits of HPV16 infection, such as an enhanced propensity to give rise to lesions evolving toward cancer.
Published: 2014
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15. Large scale genotype comparison of human papillomavirus E2-host interaction networks provides new insights for e2 molecular functions.

Author: Mandy Muller, Yves Jacob, Louis Jones, Amélie Weiss, Laurent Brino, Thibault Chantier, Vincent Lotteau, Michel Favre, and Caroline Demeret
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Human Papillomaviruses (HPV) cause widespread infections in humans, resulting in latent infections or diseases ranging from benign hyperplasia to cancers. HPV-induced pathologies result from complex interplays between viral proteins and the host proteome. Given the major public health concern due to HPV-associated cancers, most studies have focused on the early proteins expressed by HPV genotypes with high oncogenic potential (designated high-risk HPV or HR-HPV). To advance the global understanding of HPV pathogenesis, we mapped the virus/host interaction networks of the E2 regulatory protein from 12 genotypes representative of the range of HPV pathogenicity. Large-scale identification of E2-interaction partners was performed by yeast two-hybrid screenings of a HaCaT cDNA library. Based on a high-confidence scoring scheme, a subset of these partners was then validated for pair-wise interaction in mammalian cells with the whole range of the 12 E2 proteins, allowing a comparative interaction analysis. Hierarchical clustering of E2-host interaction profiles mostly recapitulated HPV phylogeny and provides clues to the involvement of E2 in HPV infection. A set of cellular proteins could thus be identified discriminating, among the mucosal HPV, E2 proteins of HR-HPV 16 or 18 from the non-oncogenic genital HPV. The study of the interaction networks revealed a preferential hijacking of highly connected cellular proteins and the targeting of several functional families. These include transcription regulation, regulation of apoptosis, RNA processing, ubiquitination and intracellular trafficking. The present work provides an overview of E2 biological functions across multiple HPV genotypes.
Published: 2012
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16. Towards a three-dimensional mapping of virus-host proximal protein interactions

Author: Yorgos Sofianatos, Étienne Coyaud, and Caroline Demeret
Abstract: Towards a three-dimensional mapping of virus-host proximal protein interactions The SARS-CoV-2 proximal interactome project sets out to build a comprehensive, three-dimensional map of protein virus-host protein interactions inside living human cells. It aims to shed light on unknown mechanisms of infection. It is made possible by a combination of advanced interactomics techniques coupled with algorithms for the 3D visualisation of networks.
Published: 2022
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17. Supplementary Table 5 from A Genomic Approach Reveals a Novel Mitotic Pathway in Papillomavirus Carcinogenesis

Author: Christian Desaintes, Sébastien Teissier, Marcella Mori, Caroline Demeret, Mohammed Abderrafi Benotmane, and Françoise Thierry
Abstract: Supplementary Table 5 from A Genomic Approach Reveals a Novel Mitotic Pathway in Papillomavirus Carcinogenesis
Published: 2023
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18. Supplementary Table 4 from A Genomic Approach Reveals a Novel Mitotic Pathway in Papillomavirus Carcinogenesis

Author: Christian Desaintes, Sébastien Teissier, Marcella Mori, Caroline Demeret, Mohammed Abderrafi Benotmane, and Françoise Thierry
Abstract: Supplementary Table 4 from A Genomic Approach Reveals a Novel Mitotic Pathway in Papillomavirus Carcinogenesis
Published: 2023
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19. Data from A Genomic Approach Reveals a Novel Mitotic Pathway in Papillomavirus Carcinogenesis

Author: Christian Desaintes, Sébastien Teissier, Marcella Mori, Caroline Demeret, Mohammed Abderrafi Benotmane, and Françoise Thierry
Abstract: More than 90% of cervical carcinomas are associated with human papillomavirus (HPV) infection. The two viral oncogenes E6 and E7 play a major role in transforming the cells by disrupting p53- and pRb-dependent cell cycle checkpoints. A hallmark of HPV-associated cervical carcinoma is loss of the expression of the viral E2 protein, often by disruption of E2-encoding gene. We showed previously that reintroduction of E2 in HPV18-associated cervical carcinoma cells induces cell cycle arrest in G1 because of the transcriptional repression of the viral oncogenes E6 and E7 and concomitant reactivation of the p53 and pRb pathways. Here we describe global gene profiling of HeLa cells expressing different HPV18 E2 mutants to study the effects of repression of the viral oncogenes. We identified 128 genes transcriptionally regulated by the viral oncogenes in cervical carcinoma. Surprisingly, E2 repressed a subset of E2F-regulated mitotic genes in an E6/E7-dependent pathway. This was corroborated by the observation that E2 delayed mitotic progression, suggesting the involvement of a mitotic pathway in HPV carcinogenesis. These mitotic genes constitute an as yet unrecognized set of genes, which were also found deregulated in other HPV-associated cervical carcinoma cell lines and therefore represent new targets for both diagnosis and therapeutic approaches in cervical cancer.
Published: 2023
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20. Supplementary Figure 6 from A Genomic Approach Reveals a Novel Mitotic Pathway in Papillomavirus Carcinogenesis

Author: Christian Desaintes, Sébastien Teissier, Marcella Mori, Caroline Demeret, Mohammed Abderrafi Benotmane, and Françoise Thierry
Abstract: Supplementary Figure 6 from A Genomic Approach Reveals a Novel Mitotic Pathway in Papillomavirus Carcinogenesis
Published: 2023
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21. Machine learning prediction of individual vaccination and infection status with respect to SARS-CoV-2. Application to the French serosurveillance survey from March 2020 to March 2022 (Preprint)

Author: Stéphanie Bougeard, Adeline Huneau-Salaun, Mickaël Attia, Jean-Baptiste Richard, Caroline Demeret, Johnny Platon, Virginie Allain, Stéphane Le Vu, Sophie Goyard, Véronique Gillon, Sibylle Bernard-Stoecklin, Bernadette Crescenzo-Chaigne, Gabrielle Jones, Nicolas Rose, Sylvie van der Werf, Olivier Lantz, Thierry Rose, and Harold Noël
Abstract: BACKGROUND The seroprevalence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in the French population was estimated with a representative, repeated cross-sectional survey based on residual sera from routine blood testing. These data had no information on infection or vaccination status, therefore limiting the ability to detail evolutions observed in the immunity level of the population over time. OBJECTIVE Our aim is to predict the infected or vaccinated status of subjects in the French serosurveillance survey only based on results of serological assays. Reference data on longitudinal serological profiles of seronegative, infected and vaccinated subjects from another French cohort were used to build the predictive model. METHODS A model of individual vaccination or infection status with respect to SARS-CoV-2  obtained from a machine learning procedure  was proposed based on three complementary serological assays. This model was applied to the French nationwide serosurveillance survey from March 2020 to March 2022 to estimate the proportions of the population that were negative, infected, vaccinated or infected and vaccinated. RESULTS From February 2021 to March 2022, the estimated percentage of infected and unvaccinated subjects in France increased from 7.5% to 16.8%. During this period, the estimated percentage increased from 3.6% to 45.2% for vaccinated and non-infected subjects, and from 2.1% to 29.1% for vaccinated and infected subjects. The major part of the decrease of the seronegative population can be attributed to vaccination. CONCLUSIONS Combining results from the serosurveillance survey with more complete data from another longitudinal cohort completes the information retrieved from serosurveillance while keeping its protocol simple and easy to implement.
Published: 2023
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22. SKAP2 Modular Organization Differently Recognizes SRC Kinases Depending on Their Activation Status and Localization

Author: Laurine Levillayer, Patricia Cassonnet, Marion Declercq, Mélanie Dos Santos, Louis Lebreton, Katerina Danezi, Caroline Demeret, Anavaj Sakuntabhai, Yves Jacob, Jean-François Bureau, Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), and Funding was provided by Institut Pasteur (Paris), Centre National de la Recherche Scientifique, Université Paris Diderot, Sorbonne Paris Cité.
Subjects: SKAP2, protein-protein interaction, luciferase complementation assay, [SDV]Life Sciences [q-bio], SRC kinase, domain architecture, Molecular Biology, Biochemistry, Analytical Chemistry
Abstract: A preprint version has been deposited to Research Square at https://doi.org/10.21203/rs.3.rs-1430558/v1; International audience; Dimerization of SRC kinase adaptor phosphoprotein 2 (SKAP2) induces an increase of binding for most SRC kinases suggesting a fine-tuning with transphosphorylation for kinase activation. This work addresses the molecular basis of SKAP2-mediated SRC kinase regulation through the lens of their interaction capacities. By combining a luciferase complementation assay and extensive site-directed mutagenesis, we demonstrated that SKAP2 interacts with SRC kinases through a modular organization depending both on their phosphorylation-dependent activation and subcellular localization. SKAP2 contains three interacting modules consisting in the dimerization domain, the SRC homology 3 (SH3) domain, and the second interdomain located between the Pleckstrin homology and the SH3 domains. Functionally, the dimerization domain is necessary and sufficient to bind to most activated and myristyl SRC kinases. In contrast, the three modules are necessary to bind SRC kinases at their steady state. The Pleckstrin homology and SH3 domains of SKAP2 as well as tyrosines located in the interdomains modulate these interactions. Analysis of mutants of the SRC kinase family member hematopoietic cell kinase supports this model and shows the role of two residues, Y390 and K7, on its degradation following activation. In this article, we show that a modular architecture of SKAP2 drives its interaction with SRC kinases, with the binding capacity of each module depending on both their localization and phosphorylation state activation. This work opens new perspectives on the molecular mechanisms of SRC kinases activation, which could have significant therapeutic impact.
Published: 2023
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23. The cargo adaptor protein CLINT1 is phosphorylated by the Numb-associated kinase BIKE and mediates dengue virus infection

Author: Stanford Schor, Szuyuan Pu, Vlad Nicolaescu, Siavash Azari, Mardo Kõivomägi, Marwah Karim, Patricia Cassonnet, Sirle Saul, Gregory Neveu, Andrew Yueh, Caroline Demeret, Jan M. Skotheim, Yves Jacob, Glenn Randall, Shirit Einav, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, University of Illinois [Chicago] (UIC), University of Illinois System, Stanford University, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and We thank investigators who have provided plasmids (see Methods). We thank Dr. Ryan Leib, Dr. Fang Liu, and the Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University Mass Spectrometry (http://mass-spec.stanford.edu) for help with relevant experiments.
Subjects: dengue virus (DENV), intracellular trafficking, [SDV]Life Sciences [q-bio], education, virus assembly, CLINT1, Cell Biology, Dengue Virus, host-pathogen interaction, Virus Replication, Biochemistry, Dengue, proteomics, Two-Hybrid System Techniques, Animals, Humans, cell signaling, NAK kinase, Phosphorylation, BIKE, Molecular Biology, human activities
Abstract: International audience; The signaling pathways and cellular functions regulated by the four Numb-associated kinases (NAKs) are largely unknown. We previously reported that AAK1 and GAK control intracellular trafficking of RNA viruses, and recently revealed a requirement for BIKE in early and late stages of dengue virus (DENV) infection. However, the downstream targets phosphorylated by BIKE in this process have not yet been identified. Here, to identify BIKE substrates, we conducted a barcode fusion genetics-yeast two-hybrid screen and retrieved publicly available data generated via affinity-purification mass spectrometry. We subsequently validated 19 of 47 putative BIKE interactors using mammalian cell-based protein-protein interaction assays. We found that CLINT1, a cargo-specific adaptor implicated in bidirectional Golgi-to-endosome trafficking, emerged as a predominant hit in both screens. Our experiments indicated that BIKE catalyzes phosphorylation of a threonine 294 (T294) CLINT1 residue both in vitro and in cell culture. Our findings revealed that CLINT1 phosphorylation mediates its binding to the DENV nonstructural 3 protein and subsequently promotes DENV assembly and egress. In addition, using live-cell imaging we revealed that CLINT1 cotraffics with DENV particles and is involved in mediating BIKE's role in DENV infection. Finally, our data suggest that additional cellular BIKE interactors implicated in the host immune and stress responses and the ubiquitin proteasome system might also be candidate phosphorylation substrates of BIKE. In conclusion, these findings reveal cellular substrates and pathways regulated by the understudied NAK enzyme BIKE, a mechanism for CLINT1 regulation, and control of DENV infection via BIKE signaling, with potential implications for cell biology, virology, and host-targeted antiviral design.
Published: 2022
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24. Two SKAP2 modular organizations differently recognize SRC kinases depending on their activation status and localization

Author: Laurine Levillayer, Patricia Cassonnet, Marion Declercq, Mélanie Dos Santos, Louis Lebreton, Katerina Danezi, Caroline Demeret, Anavaj Sakuntabhai, Yves Jacob, and Jean-François Bureau
Abstract: Background: The activation of SRC kinases by trans-phosphorylation raises the question of their interplay. This work addresses this question by studying the interactions of SRC kinases with the SRC Kinase Adaptor Phosphoprotein 2 (SKAP2) by combining a luciferase complementation assay and extensive site-directed mutagenesis. Results: SKAP2 interacts with SRC kinases through two different module organizations that have different affinities for the activated and non-activated kinase conformations. The DIM domain of SKAP2 is necessary and sufficient to bind to most activated SRC kinases. A second SKAP2 module organization for binding to SRC kinases at their steady state is composed of the DIM and SH3 domains as well as the linker located between the PH and the SH3 domains. Classical binding sites of the PH and SH3 domains and the tyrosines located inside linkers modulate these interactions. Analysis of HCK mutants supports this model and shows the role of two residues, Y390 and K7, on its degradation following activation. Conclusion: In this article, we show that SKAP2 have a modular architecture composed of 2 domains and one interdomain to interact with SRC kinases, which binding capacity of each module depends on their localization and activation. This work opens new perspectives on how activation of SRC kinases occurs, which could have new and interesting therapeutic consequences.
Published: 2022
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25. OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1

Author: Qi Wen Teo, Adolfo García-Sastre, Leo L.M. Poon, Ho Him Wong, Caroline Demeret, Agathe Le Quang, Artejan te Velthuis, Akhee Sabiha Jahan, Elise Biquand, Alex W.H. Chin, Sumana Sanyal, Sophie A. Valkenburg, Chris Ka Pun Mok, Raquel Muñoz-Moreno, Centre de recherche Université de Hong-Kong-Pasteur, Réseau International des Instituts Pasteur (RIIP), LKS Faculty of Medicine (HKU Med), The University of Hong Kong (HKU), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Addenbrooke's Hospital, Cambridge University NHS Trust, This work was funded by Research Grants Council (GRF) grants 17113915 and 17112617 and partially supported by Health and Medical ResearchFunds (16150592), a theme-based research grant from the ResearchGrants Council (project T11-705/14N), and PTR (546) from Institut Pasteur.S.S. is supported by the Croucher Foundation., Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], te Velthuis, Arend [0000-0002-5129-3953], and Apollo - University of Cambridge Repository
Subjects: Male, 0301 basic medicine, Viral pathogenesis, viruses, Regulator, Viral Nonstructural Proteins, Madin Darby Canine Kidney Cells, Cytosol, 0302 clinical medicine, Ubiquitin, Interferon, Receptors, Immunologic, influenza A, lcsh:QH301-705.5, Deubiquitinating Enzymes, biology, Chemistry, RIG-I, deubiquitylases, NF-kappa B, virus diseases, 3. Good health, Cell biology, Cysteine Endopeptidases, OTUB1, Interferon Type I, Mitochondrial Membranes, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, DEAD Box Protein 58, Signal transduction, Signal Transduction, medicine.drug, Proteasome Endopeptidase Complex, RNA virus, chemical and pharmacologic phenomena, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Dogs, Influenza, Human, medicine, Animals, Humans, ubiquitylation, biochemical phenomena, metabolism, and nutrition, viral subversion strategies, HEK293 Cells, 030104 developmental biology, lcsh:Biology (General), A549 Cells, Proteolysis, biology.protein, innate immune response, Interferon Regulatory Factor-3, Protein Multimerization, RIG-I signaling, IRF3, Gene Deletion, 030217 neurology & neurosurgery
Abstract: Summary: Deubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, systematic analyses of DUBs that regulate this pathway have not been performed. Using a ubiquitin C-terminal electrophile, we profile DUBs that function during influenza A virus (IAV) infection and isolate OTUB1 as a key regulator of RIG-I-dependent antiviral responses. Upon infection, OTUB1 relocalizes from the nucleus to mitochondrial membranes together with RIG-I, viral PB2, and NS1. Its expression depends on competing effects of interferon stimulation and IAV-triggered degradation. OTUB1 activates RIG-I via a dual mechanism of K48 polyubiquitin hydrolysis and formation of an E2-repressive complex with UBCH5c. We reconstitute this mechanism in a cell-free system comprising [35S]IRF3, purified RIG-I, mitochondrial membranes, and cytosol expressing OTUB1 variants. A range of IAV NS1 proteins trigger proteasomal degradation of OTUB1, antagonizing the RIG-I signaling cascade and antiviral responses. : Jahan et al. describe the role of Otub1, a deubiquitylase that is induced during virus infection in an interferon-dependent manner to regulate optimal signaling via the RIG-I pathway. Influenza A virus NS1 is able to bind and degrade newly synthesized Otub1 as a means to evade the innate immune response. Keywords: deubiquitylases, RIG-I signaling, ubiquitylation, innate immune response, RNA virus, influenza A, viral subversion strategies
Published: 2020
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26. A screening pipeline identifies a broad-spectrum inhibitor of bacterial AB toxins with cross protection against influenza A virus H1N1 and SARS-CoV-2

Author: Yu Wu, Nassim Mahtal, Léa Swistak, Sara Sagadiev, Mridu Acharya, Caroline Demeret, Sylvie van der Werf, Florence Guivel-Benhassine, Olivier Schwartz, Serena Petracchini, Amel Mettouchi, Eléa Paillares, Lucie Caramelle, Pierre Couvineau, Robert Thai, Peggy Barbe, Mathilde Keck, Priscille Brodin, Arnaud Machelart, Valentin Sencio, François Trottein, Martin Sachse, Gaëtan Chicanne, Bernard Payrastre, Florian Ville, Victor Kreis, Michel-Robert Popoff, Ludger Johannes, Jean-Christophe Cintrat, Julien Barbier, Daniel Gillet, and Emmanuel Lemichez
Subjects: Diphtheria toxin, biology, Toxin, Endosome, Chemistry, Toxin transport, Shiga toxin, medicine.disease_cause, Microbiology, PIKFYVE, AB toxin, biology.protein, Influenza A virus, medicine
Abstract: A challenge for the development of host-targeted anti-infectives against a large spectrum of AB-like toxin-producing bacteria encompasses the identification of chemical compounds corrupting toxin transport through both endolysosomal and retrograde pathways. Here, we performed a high-throughput screening of small chemical compounds blocking active Rac1 proteasomal degradation triggered by the Cytotoxic Necrotizing Factor-1 (CNF1) toxin, followed by orthogonal screens against two AB toxins hijacking defined endolysosomal (Diphtheria toxin) or retrograde (Shiga-like toxin 1) pathways to intoxicate cells. This led to the identification of the molecule N-(3,3-diphenylpropyl)-1-propyl-4-piperidinamine, referred to as C910. This compound induces the swelling of EEA1-positive early endosomes, in absence of PIKfyve kinase inhibition, and disturbs the trafficking of CNF1 and the B-subunit of Shiga toxin along the endolysosomal or retrograde pathways, respectively. Together, we show that C910 protects cells against 8 bacterial AB toxins including large clostridial glucosylating toxins from Clostridium difficile. Of interest, C910 also reduced viral infection in vitro including influenza A virus subtype H1N1 and SARS-CoV-2. Moreover, parenteral administration of C910 to the mice resulted in its accumulation in lung tissues and reduced lethal influenza infection.
Published: 2021
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27. Prevalence of SARS-CoV-2 antibodies in France: results from nationwide serological surveillance

Author: Louise Perrin de Facci, Virgile Monnet, Pierre Charneau, Caroline Demeret, Jean-Baptiste Richard, Nicolas Escriou, Daniel Lévy-Bruhl, Gabrielle Jones, Thierry Rose, François Anna, Yvonnick Guillois, Marion Gransagne, Corinne Robin, Sophie Goyard, Stéphane Petres, Stéphane Le Vu, Marie-Noëlle Ungeheuer, Lucie Léon, Laurent Filleul, Sylvie van der Werf, Sibylle Bernard-Stoecklin, Olivier Helynck, Harold Noel, Santé publique France - French National Public Health Agency [Saint-Maurice, France], Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, Institut Pasteur [Paris], Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris]-TheraVectys, Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Chimie et Biocatalyse, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratoire CERBA [Saint Ouen l'Aumône], Biomnis Sample Library (BSL), Eurofins Biomnis, Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR), We thank Christine Larsen, Bruno Coignard and Jean-Claude Desenclos (Santé publiqueFrance) for their helpful contribution at setting up the study, from Institut Pasteur,Isabelle Cailleau for support in the funding process, Hélène Munier-Lehmann for accessto automate and supply management at the Unit of Chemistry and Biocatalysis, Yves L.Janin for providing the luciferase prosubstrate hikarazine 108, Philippe Souque forproduction of the lentiviral pseudo-types, the whole ICAReB team and COVID-19support staff for sample management at Institut Pasteur, Juliette Paireau (Institut Pas-teur, Santé publique France), Rodolphe Thiébaut (Bordeaux Université) and Xavier deLamballerie (Aix-Marseille Université) for valuable comments onfirst results. We alsothank the team from the Eurofins Biomnis Sample Library and from CerbaHealthcareBenedicte Roquebert (Laboratoire Cerba) and Marie Pierre Guerra (CerbaXpert) forcontributing to sample collection. Santé publique France provided funding to the NRCand to the two centralising biobanks to cover sample collection, preparation, transportand analysis costs. The funder had no role in analysis, interpretation of data or writing ofthe report. S.L.V., G.J. and H.N. had full access to all the data and had responsibility tosubmit for publication., Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-TheraVectys, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Lassailly-Bondaz, Anne, Santé publique France - French National Public Health Agency, Centre National de Référence des virus des infections respiratoires (dont la grippe) [Paris] (CNR), Santé publique France, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: 0301 basic medicine, Male, Epidemiology, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Antibodies, Viral, Serology, 0302 clinical medicine, Seroepidemiologic Studies, Case fatality rate, Prevalence, Cumulative incidence, 030212 general & internal medicine, Child, Aged, 80 and over, 0303 health sciences, education.field_of_study, Multidisciplinary, biology, Transmission (medicine), Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Child, Preschool, Female, France, medicine.symptom, Antibody, Adult, medicine.medical_specialty, Adolescent, Science, Population, Asymptomatic, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Young Adult, medicine, Seroprevalence, Humans, education, Epidemics, 030304 developmental biology, Aged, business.industry, SARS-CoV-2, Public health, Infant, Newborn, COVID-19, Infant, General Chemistry, 030104 developmental biology, Viral infection, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, biology.protein, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Demography
Abstract: Assessment of the cumulative incidence of SARS-CoV-2 infections is critical for monitoring the course and extent of the COVID-19 epidemic. Here, we report estimated seroprevalence in the French population and the proportion of infected individuals who developed neutralising antibodies at three points throughout the first epidemic wave. Testing 11,000 residual specimens for anti-SARS-CoV-2 IgG and neutralising antibodies, we find nationwide seroprevalence of 0.41% (95% CI: 0.05–0.88) mid-March, 4.14% (95% CI: 3.31–4.99) mid-April and 4.93% (95% CI: 4.02–5.89) mid-May 2020. Approximately 70% of seropositive individuals have detectable neutralising antibodies. Infection fatality rate is 0.84% (95% CI: 0.70–1.03) and increases exponentially with age. These results confirm that the nationwide lockdown substantially curbed transmission and that the vast majority of the French population remained susceptible to SARS-CoV-2 in May 2020. Our study shows the progression of the first epidemic wave and provides a framework to inform the ongoing public health response as viral transmission continues globally., The percentage of national populations infected during the first stages of the COVID-19 pandemic are unclear owing to limited early testing. Here the authors provide a nation-wide prevalence study of SARS-CoV-2 antibodies in France from the first wave of COVID-19 in 2020, including stratification based on age, sex and region.
Published: 2021
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28. High-risk exposure without personal protective equipment and infection with SARS-CoV-2 in healthcare workers: results of the CoV-CONTACT prospective cohort

Author: Yazdan Yazdanpanah, Patricia Bruijning-Verhagen, Charles Burdet, Xavier Duval, Jeremie Guedj, Thierry Rose, Sarah Tubiana, Sylvie van der Werf, Julia Bielicki, Pauline Manchon, François Blanquart, Sylvie Behillil, Loubna Alavoine, Diane Descamps, Anne Leclercq, Herman Goossens, Jean-Christophe Lucet, Mickael Attia, Michael Thy, Caroline Demeret, Charlotte Charpentier, N. Houhou, Bruno Lina, Centre d'Investigations Cliniques [CHU Bichat] (CIC plurithématique), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Centre de Ressources Biologiques [CHU Bichat], Département d'Epidemiologie, Biostatistique et Recherche Clinique (DEBRC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Virologie [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Institut Pasteur [Paris] (IP), Hôpital Beaujon [AP-HP], Services de Maladies Infectieuses et Tropicales [CHU Bichat], Physique des fonctions biologiques / Physics of Biological Functions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Infection and Immunity [Londres, UK], St George's, University of London, University Children’s Hospital Basel = Hôpital pédiatrique universitaire des deux Bâle [Bâle, Suisse] (UKBB), Julius Center for Health Sciences and Primary Care, University Medical Center [Utrecht], Vaccine & Infectious Disease Institute [Antwerp, Belgium] (VAXINFECTIO), University of Antwerp (UA), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des Virus des Infections Respiratoires (dont la Grippe) [Lyon] (CNR - laboratoire associé), Institut des Agents Infectieux [Lyon] (IAI), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), The study was founded by Reacting, the French Ministry of Health (PHRC-N COVID-19, project PHRC-20-0242) and the European Commission (RECoVer, grant agreement 101003589). Some authors received financial support of the national research agency (ANR) through the ANR-Flash calls for COVID-19 (TheraCoV ANR-20-COVI-0018), ANR-20-COVI-0018,TheraCoV,Dynamique virale au niveau individuel et populationnel : implications pour l'optimisation des stratégies antivirales(2020), European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR), Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des Virus des Infections Respiratoires (dont la Grippe) [Lyon] (CNR), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], demeret, caroline, Dynamique virale au niveau individuel et populationnel : implications pour l'optimisation des stratégies antivirales - - TheraCoV2020 - ANR-20-COVI-0018 - COVID-19 - VALID, Rapid European COVID-19 Emergency Response research - RECOVER - - H2020-SC1-PHE-CORONAVIRUS-20202020-02-14 - 2022-02-13 - 101003589 - VALID, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, business.industry, SARS-CoV-2, healthcare workers, Risk of infection, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], 030231 tropical medicine, Pharmacist, transmission, 3. Good health, Serology, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Health care, high-risk exposure, personal protective equipment, Medicine, 030212 general & internal medicine, Seroconversion, business, Prospective cohort study, Personal protective equipment
Abstract: ObjectiveWe aimed to estimate the risk of infection in Healthcare workers (HCWs) following a high-risk exposure without personal protective equipment (PPE).MethodsWe conducted a prospective cohort in HCWs who had a high-risk exposure to SARS-CoV-2-infected subject without PPE. Daily symptoms were self-reported for 30 days, nasopharyngeal swabs for SARS-CoV-2 RT-PCR were performed at inclusion and at days 3, 5, 7 and 12, SARS-CoV-2 serology was assessed at inclusion and at day 30. Confirmed infection was defined by positive RT-PCR or seroconversion, and possible infection by one general and one specific symptom for two consecutive days.ResultsBetween February 5thand May 30th, 2020, 154 HCWs were enrolled within 14 days following one high-risk exposure to either a hospital patient (70/154; 46.1%) and/or a colleague (95/154; 62.5%). At day 30, 25.0% had a confirmed infection (37/148; 95%CI, 18.4%; 32.9%), and 43.9% (65/148; 95%CI, 35.9%; 52.3%) had a confirmed or possible infection. Factors independently associated with confirmed or possible SARS-CoV-2 infection were being a pharmacist or administrative assistant rather than being from medical staff (adjusted OR (aOR)=3.8, CI95%=1.3;11.2, p=0.01), and exposure to a SARS-CoV-2-infected patient rather than exposure to a SARS-CoV-2-infected colleague (aOR=2.6, CI95%=1.2;5.9, p=0.02). Among the 26 HCWs with a SARS-CoV-2-positive nasopharyngeal swab, 7 (26.9%) had no symptom at the time of the RT-PCR positivity.ConclusionsThe proportion of HCWs with confirmed or possible SARS-CoV-2 infection was high. There were less occurrences of high-risk exposure with patients than with colleagues, but those were associated with an increased risk of infection.
Published: 2021

29. A map of binary SARS-CoV-2 protein interactions implicates host immune regulation and ubiquitination

Author: Isaiah Hazelwood, Dayag Sheykhkarimli, Jean-Claude Twizere, Michael A. Calderwood, Nishka Kishore, Atina G. Cote, Florent Laval, Pascal Falter-Braun, Luc Willems, Marc Vidal, Benjamin Weller, Ashyad Rayhan, Patricia Cassonnet, Frederick P. Roth, Claudia Falter, Tong Hao, Veronika Young, Melina Altmann, Rothballer Simin, Nora Marín-de la Rosa, Jennifer J. Knapp, Alexandra Strobel, Ramakrishnan Pandiarajan, Caroline Demeret, Kerstin Spirohn, Dave E Hill, Mayra Sauer, Patricia A Rodriguez Coloma, Oxana Pogoutse, Guillaume Dugied, Patrick Schwehn, Roujia Li, Dae-Kyum Kim, Lena Elorduy Vergara, Maria Nguyen, Chung Wen Lin, Bingruo B Liu, Yves Jacob, Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], University of Toronto, Technical University of Munich (TUM), Institute of Network Biology, Helmholtz Zentrum München (HMGU), Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute [Boston]-Department of Cancer Biology, GIGA [Université Liège], Université de Liège, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Paris (UP), Blavatnik Institute [Boston], Harvard Medical School [Boston] (HMS), Ludwig-Maximilians-Universität München (LMU), This work was supported by a Canadian Institutes for Health Research Foundation Grant (F.P.R.), the Canada Excellence Research Chairs Program (F.P.R.), the Thistledown Foundation (F.P.R.), the LabEx Integrative Biology of Emerging Infectious Diseases (10-LABX-0062, Y.J.) and Platform for EuropeanPreparedness Against (Re-)emerging Epidemics, EU (602525, Y.J.), the European Union’s Horizon 2020 Research and Innovation Programme (Project ID 101003633, RiPCoN, P.FB, C.B., P.A.). F.L. was supported by a Belgian American Educational Foundation Doctoral Research Fellowship and aWallonia-Brussels International (WBI)-World Excellence Fellowship. M.V. is a Chercheur Qualifié Honoraire from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation,Belgium)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Université Paris Cité (UPCité)
Subjects: 0303 health sciences, Immune signaling, Host (biology), physical protein interaction, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), viruses, membrane trafficking, [SDV]Life Sciences [q-bio], 030302 biochemistry & molecular biology, COVID-19, Inflammation, Computational biology, Biology, Protein ubiquitination, Protein–protein interaction, 03 medical and health sciences, protein ubiquitination, Immune system, medicine, immune signaling, medicine.symptom, Host protein, 030304 developmental biology
Abstract: Key steps in viral propagation, immune suppression, and pathology are mediated by direct, binary, physical interactions between viral and host proteins. To understand the biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we generated an unbiased systematic map of binary interactions between viral and host proteins, complementing previous co-complex association maps by conveying more direct mechanistic understanding and potentially enabling targeted disruption of direct interactions. To this end, we deployed two parallel strategies, identifying 205 virus-host and 27 intraviral binary interactions amongst 171 host and 19 viral proteins, and confirming high quality of these interactions via a calibrated orthogonal assay. Host proteins interacting with SARS-CoV-2 proteins are enriched in various cellular processes, including immune signaling and inflammation, protein ubiquitination, and membrane trafficking. Specific subnetworks provide new hypotheses related to viral modulation of host protein homeostasis and T-cell regulation. The binary virus-host protein interactions we identified can now be prioritized as targets for therapeutic intervention. More generally, we provide a resource of systematic maps describing which SARS-CoV-2 and human proteins interact directly.
Published: 2021

30. SARS-CoV-2 infection in schools in a northern French city: a retrospective serological cohort study in an area of high transmission, France, January to April 2020

Author: Ludivine Grzelak, Charlotte Renaudat, Yoann Madec, Lucie Kuhmel, Laurence Arowas, Caroline Demeret, Kuang-Yu Chen, Christèle Huon, Marie Noelle Ungeheuer, Marc Eloit, Olivier Schwartz, Thomas Bigot, Bernadette Crescenzo-Chaigne, Sandrine Fernandes Pellerin, Arnaud Fontanet, Isabelle Staropoli, Bruno Hoen, Nathalie Jolly, Camille Besombes, Sandie Munier, Isabelle Cailleau, Timothée Bruel, Pierre Charneau, Laura Tondeur, Sarah Temmam, Blanca Liliana Perlaza, Rebecca Grant, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité - Virus and immunity, Université de Paris (UP), Direction de la recherche médicale de l'Institut Pasteur, Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Centre Médical de l'Institut Pasteur, Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biologie des ARN et virus influenza - RNA Biology of Influenza Virus, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris]-TheraVectys, Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, École nationale vétérinaire d'Alfort (ENVA), The study was funded by Institut Pasteur, and several laboratories participating in the study receive funding from the Labex IBEID (ANR-10-LABX-62-IBEID), REACTing and the INCEPTION project (PIA/ANR-16-CONV-0005) for studies focusing on emerging viruses. OS lab is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro- Immuno' ANR-14-CE14-0015-01 and the Gilead HIV cure program. LG is supported by the French Ministry of Higher Education, Research and Innovation. ME lab is funded by Institut Pasteur, Labex IBEID (ANR-10-LABX-62-IBEID), REACTing (Research & Action Emerging Infectious Diseases), EU Grant 101003589 RECoVER., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Université Paris Cité (UPCité), Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École nationale vétérinaire - Alfort (ENVA), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Vaccine Research Institute [Créteil, France] (VRI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-TheraVectys
Subjects: 0301 basic medicine, Emerging infectious diseases, medicine.medical_specialty, MESH: Schools, Epidemiology, [SDV]Life Sciences [q-bio], Context (language use), Asymptomatic, Serology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Virology, MESH: Child, Humans, Medicine, MESH: COVID-19, MESH: SARS-CoV-2, 030212 general & internal medicine, Child, MESH: Cohort Studies, Retrospective Studies, Schools, MESH: Humans, Transmission (medicine), business.industry, SARS-CoV-2, Research, 4. Education, Public Health, Environmental and Occupational Health, COVID-19, Outbreak, Retrospective cohort study, MESH: Retrospective Studies, 3. Good health, Coronavirus disease 2019 (COVID-19), MESH: France, 030104 developmental biology, France, medicine.symptom, business, Demography, Cohort study
Abstract: Background Children’s role in SARS-CoV-2 epidemiology remains unclear. We investigated an initially unnoticed SARS-CoV-2 outbreak linked to schools in northern France, beginning as early as mid-January 2020. Aims This retrospective observational study documents the extent of SARS-CoV-2 transmission, linked to an affected high school (n = 664 participants) and primary schools (n = 1,340 study participants), in the context of unsuspected SARS-CoV-2 circulation and limited control measures. Methods Between 30 March and 30 April 2020, all school staff, as well as pupils and their parents and relatives were invited for SARS-CoV-2 antibody testing and to complete a questionnaire covering symptom history since 13 January 2020. Results In the high school, infection attack rates were 38.1% (91/239), 43.4% (23/53), and 59.3% (16/27), in pupils, teachers, and non-teaching staff respectively vs 10.1% (23/228) and 12.0% (14/117) in the pupils’ parents and relatives (p Conclusions Viral circulation can occur in high and primary schools so keeping them open requires consideration of appropriate control measures and enhanced surveillance.
Published: 2021
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31. Nasopharyngeal and serological anti SARS-CoV-2 IgG/IgA responses in COVID-19 patients

Author: Sylvie van der Werf, Caroline Demeret, Bernadette Crescenzo-Chaigne, Lila Bouadma, Jade Ghosn, Vincent Enouf, Sarah Tubiana, Stéphane Petres, Marie Noelle Ungeheuer, Sylvie Behillil, Nicolas Escriou, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR), Institut Pasteur [Paris], Plateforme de Microbiologie Mutualisée (PIBnet) - Mutualized Platform for Microbiology (P2M), Laboratoire d’innovation : vaccins – Innovation lab : vaccines, Plateforme technologique Production et purification de protéines recombinantes – Production and Purification of Recombinant Proteins Technological Platform (PPR), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Université Sorbonne Paris Nord, Services de Maladies Infectieuses et Tropicales [CHU Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigations Cliniques [CHU Bichat] (CIC plurithématique), This work was supported by the « URGENCE COVID-19 » fundraising campaign of Institut Pasteur, by REACTING (Research & Action Emerging Infectious Diseases) and by the H2020 project 101003589 (RECOVER). The French Covid Cohort is funded through the Ministry of Health and Social Affairs (PHRC n°20-0424) and Ministry of Higher Education and Research dedicated COVID19 fund., List of the membership of the French COVID cohort study group : Mélanie RORIZ, Patrick RISPAL, Sarah REDL (CHG d'Agen), Laurent LEFEBVRE, Pascal GRANIER, Laurence MAULIN (CH du Pays d'Aix, Aix en Provence), Cédric JOSEPH, Julien MOYET, Sylvie LION-DAOLIO (CHU Amiens Nord), Rafael MAHIEU, Alexandra DU-CANCELLE, Vincent DUBEE (CHU d'Angers), Stéphane SALLA-BERRY, Aldric MANUEL, Gabriel MACHEDA, Mylène MAILLET, Bruno CHANZY (CH d'Annecy Genevois), Jean-Charles GAGNARD (Hôpital privé d'Antony), Guillermo GIORDANO, Clara MOUTON PERROT, Vincent PESTRE (CH Henri Duffaut, Avignon), Cécile FICKO, Marie GOMINET, Aurore BOUSQUET (Hôpital d'instruction des armées Begin), Charline VAUCHY, Kévin BOUILLER, Maïder PAGADOY, Solène MARTY-QUINTERNET, Quentin LEPILLER (CHU Jean Minjoz, Besançon), Cyril LE BRIS, Benoit THILL, Marie-Laure CASANOVA, Georges LE FALHER, Eric OZIOL (CH de Béziers), Hugues CORDEL, Nathalie DOURNON, Olivier BOUCHAUD, Ségolène BRICHLER (Hôpital Avicenne, Bobigny), Duc NGUYEN, Pantxika BELLECAVE, Camille CICCONE, Marie-Edith LAFON (CHU Pellegrin, Bordeaux), Ségolène GREFFE (CHU Ambroise Paré, Boulogne Billancourt), Camille BOUISSE, Nicholas SEDILLOT, Damien BOUHOUR (CH Fleyriat, Bourg en Bresse), Camille CHASSIN (CH Pierre Oudot, Bourgoin-Jallieu), Erwan L'HER, Séverine ANSART, Cécile TROMEUR, Dewi GUELLEC (CHRU de Brest), Antoine MERCKX (CH de Cahors), Felix DJOSSOU (CH Andrée Rosemon, Cayenne), Vincent PEIGNE, Carola PIEROBON, Marie-Christine CARRET, Florence JEGO, Margaux ISNARD (CHMS Chambéry NH), Johann AUCHABIE, Roxane COURTOIS (CH de Cholet), Olivier LESENS (CHU Gabriel Montpied, Clermont-Ferrand), Martin MARTINOT (Hôpital Pasteur, Colmar), Olivier PICONE (Hôpital Louis Mourier, Colombes), Marie LACOSTE (CH Alpes Leman Contamine sur Arve), Brigitte ELHAR-RAR, Valérie GARRAIT, Isabelle DELACROIX, Thomas MAITRE, Jean Baptiste ASSIE (Centre Hospitalier Intercommunal de Créteil), Elsa NYAMANKOLLY (CH de Dax), François Xavier CATHERINE, Ma-thieu BLOT, Sophie MAHY, Marielle BUISSON, Lionel PIROTH, Florence GUILLOTIN, Alexis DE ROUGEMONT (CHU de Dijon Bourgogne), Valentine CAMPANA, Jérémie PASQUIER, André CABIE (CHU de Martinique, Fort de France), Simon BESSIS (Hôpital Raymond Poincaré, Garches), Olivier EPAULARD, Nicolas TERZI, Jean-François PAYEN, Laurence BOUILLET, Rebecca HAMIDFAR, Marion Le MARECHAL (CHU de Grenoble), Moïse MACHADO, Audrey BARRELET, Alexandra BEDOSSA (Grand Hôpital de l'Est Francilien site Marne-la-Vallée, Jossigny), Gwenhaël COLIN, Romain DECOURS, Thomas GUIMARD (CHD Les Oudairies, La Roche Sur Yon), Cécile GOUJARD, Stéphane JAUREGUIBERRY, Antoine CHERET (Hôpital Universitaire Bicêtre, Le Kremlin-Bicêtre), Anne Sophie RESSEGUIER (CH Emile Roux, Le Puy en Velay), Julien POISSY, Daniel MATHIEU, Saad NSEIR, Ilka ENGELMANN, Martine REMY (CHRU de Lille, Hôpital Salengro), Fanny VUOTTO, Benoit GACHET, Karine FAURE, Marielle BOYER-BESSEYRE, Kazali Enagnon (CHRU de Lille, Hôpital Fourrier), Marc LAMBERT, Arnaud SCHERPEREEL, Dominique DEPLANQUE, Stéphanie FRY, Cécile YELNIK (CHRU de Lille, Hôpital Albert Calmette), Laurent BITKER, Mehdi MEZIDI, Hodane YONIS, Nicolas BENECH, Thomas PERPOINT, Anne CONRAD, Vinca ICARD, Martine VALETTE (Hôpital de la Croix Rousse, Lyon), Simon-Djamel THIBERVILLE (Hôpital Louis Raffalli, Manosque), Stanislas REBAUDET (Hôpital Européen de Marseille), Bertrand DUSSOL (Hôpital Conception, Marseille), Sylvain DIAMANTIS, Catherine CHAKVEATZE, Clara FLATEAU (Groupe Hospitalier Sud Ile De France, hôpital de Melun), Vincent DINOT, Rostane GACI, Nadia OUAMARA (Hôpital de Mercy, CHR Metz-Thionville, Ars laquenexy), Hajnal-Gabriela ILLES, Louis GER-BAUD MORLAES, Jérôme DIMET (CH de Mont Marsan), Vincent LE MOING, Nathalie PANSU, Clément LE BIHAN, Brigitte MONTES (CHU de Montpellier), Anne Sophie BOUREAU, Clotilde ALLAVENA, Sabelline BOUCHEZ, Romain GUERY, Paul LE TURNIER, Cécile MEAR-PASSARD, Virginie FERRE (CHU de Nantes), Christophe RAPP (Hôpital Américain de Paris, Neuilly sur Seine), Elisa DE-MONCHY, Céline MICHELANGELLI, Karine RISSO (CHU de Nice), Paul LOUBET, Jean-Phillippe LAVIGNE (CHU Caremeau, Nîmes), Etienne DE MONTMOLLIN, Juliette PATRIER, Paul Henri WICKY, Lucie LE FEVRE, Pierre JACQUET, Raphael BORIE, Antoine DOSSIER, Dominique LUTON, Valentina ISERNIA, Sylvie LE GAC (Hôpital Bichat, Paris), Cécile AZOULAY, Nicolas CARLIER, Liem LUONG, Marie LACHATRE, Odile LAUNAY (Hôpital Cochin, Paris), Younes KERROUMI, Vanina MEYSSONNIER (Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris), Jean-Luc DIEHL, Jean-Sébastien HULOT, Bernard CHOLLEY, Jean-Benoît ARLET, Olivier SANCHEZ (Hôpital Européen Georges Pompidou, Paris), Victoria MANDA, Laurène AZEMAR, Guylaine CASTOR-ALEXANDRE (Hôpital Lariboisière, Paris), Karine LACOMBE, Thibault CHIARABINI, Bénédicte LEFEBVRE, Laurence MORAND-JOUBERT, Djeneba FOFANA, Aurélie SCHNURIGER (Hôpital Saint Antoine, Paris), Nathalie DE CASTRO, Constance DELAUGERRE, Marie-Laure CHAIX (Hôpital Saint Louis, Paris), Julie CHAS (Hôpital Tenon, Paris), Valérie GABORIEAU, Eve LE COUSTUMIER, Walter PICARD (CH de Pau), Jean-Benoît ZABBE, Florent PEELMAN, Edouard SOUM (CH de Périgueux), Hugues AUMAÎTRE (CH de Perpignan), Elodie CURLIER, Rachida OUISSA, Isabelle FABRE (CHU de Pointe à Pitre, Guadeloupe), Blandine RAMMAERT (CHU de Poitiers), Nadia SAIDANI (CH Quimper), Firouzé BANI-SADR, Maxime HENTZIEN, Yohan N 'GUYEN, Juliette ROMARU, Kévin DIDIER (CHU Reims), Isabelle ENDERLE, Vincent THIBAULT, Fabrice LAINE, Matthieu LESOU-HAITIER, Matthieu REVEST, Pierre TATTEVIN (CHU Rennes), Jean-Christophe PLANTIER, Manuel ETIENNE, Véronique LEMEE, Eglantine FERRAND DEVOUGE, Kévin ALEXANDRE, Elise ARTAUD-MACCARI (CHU Rouen), Nathalie ALLOU, Marie LAGRANGE, Julien JABOT (CH Saint Denis et Saint Pierre, La réunion), Benoît ROZE, Delphine BREGEAUD, Younes AIT TAMLIHAT (CH Saintes), Ali HACHEMI (CH Soisson), Hélène SALVATOR, Erwan FOURN, David ZUCMAN (Hôpital Foch, Suresnes), Eric DELAVEUVE, Coline JAUD-FISCHER, Paul DUNAND (Hôpital Bel Air, Thionville), François BISSUEL (CH Thonon les Bains), Karen DELAVIGNE, Marie PIEL-JULIAN, Pierre DELOBEL, Benjamine SARTON, Marie RAFIQ, Guillaume MARTIN-BLONDEL, Laurent GUILLEMINAULT, Marlène MURRIS, Agnès SOMMET (CHU de Toulouse), Eric SENNEVILLE, Olivier ROBINEAU, Agnès MEYBECK (CH Tourcoing), Denis GAROT, Laurent PLANTIER, Valérie GISSOT, Julien MARLET, Karl STEFIC, Catherine GAUDY-GRAFFIN, Francis BARIN, Adrien LEMAIGNEN (CHU Bretonneau, Tours), Grégory CORVAISIER, Delphine LARIVIERE, Marie LANGELOT-RICHARD (CH Vannes), Elisabeth BOTELHO-NEVERS , Amandine GAGNEUX-BRUNON, Tiffany TROUILLON, Thomas BOURLET, Thomas BOURLET, Sylvie PILLET, Bruno POZZETTO (CHU de St Etienne), Antoine KIMMOUM, Bruno LEVY, Mathieu MATTEI, François GOEHRINGER, Christian RABAUD, Sibylle BEVILACQUA, Benjamin LEFEVRE, Anne GUILLAUMOT, Véronique VENARD, Hélène JEULIN, Evelyne SCHVOERER, Cédric HARTARD (CHU de Nancy, Vandoeuvre les Nancy), Pauline CARAUX PAZ, Laurent RICHIER, Mohamed EL SANHARAWI (CH Villeneuve St Georges)., European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord
Subjects: Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Severe disease, Infectious and parasitic diseases, RC109-216, Article, Serology, 03 medical and health sciences, 0302 clinical medicine, Medicine, Mucosal Immunity, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, business.industry, Epithelium, 3. Good health, Nucleoprotein, medicine.anatomical_structure, Antibody response, SARS CoV, 030220 oncology & carcinogenesis, Immunology, biology.protein, Antibody, business
Abstract: BackgroundThe systemic antibody responses to SARS-CoV-2 in COVID-19 patients has been extensively studied. However, much less is known about the mucosal responses in the upper airways at the site of initial SARS-CoV-2 replication. Local antibody responses in the nasopharyngeal epithelium, that are likely to determine the course of infection, have not been analysed so far nor their correlation with antibody responses in serum.MethodsThe IgG and IgA antibody responses were analysed in the plasma as well as in nasopharyngeal swabs (NPS) from the first four COVID-19 patients confirmed by RT-qPCR in France. Two were pauci-symptomatic while two developed severe disease. Taking advantage of a comprehensive series of plasma and nasopharyngeal samples, we characterized their antibody profiles from the second week post symptoms onset, by using an in-house ELISA to detect anti-SARS-CoV-2 Nucleoprotein (N) IgG and IgA.ResultsAnti-N IgG and IgA antibodies were detected in the NPS of severe patients. Overall, the levels of IgA and IgG antibodies in plasma and NPS appeared specific to each patient.ConclusionsAnti-N IgG and IgA antibodies are detected in NPS, and their levels are related to antibody levels in plasma. The two patients with severe disease exhibited different antibody profiles that may reflect different disease outcome. For the pauci-symptomatic patients, one showed a low anti-N IgG and IgA response in the plasma only, while the other one did not exhibit overt serological response.
Published: 2021
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32. Cluster of COVID-19 in northern France: A retrospective closed cohort study

Author: Nathalie Jolly, Christèle Huon, Laura Tondeur, Bernadette Crescenzo, Sarah Temmam, Sandie Munier, Camille Besombes, Isabelle Staropoli, Timothée Bruel, Isabelle Cailleau, Rebecca Grant, Pierre Gallian, Simon Cauchemez, Marie-Noëlle Ungeheuer, Yoann Madec, Sylvie van der Werf, Bruno Hoen, Ludivine Grzelak, Marc Eloit, Sandrine Fernandes Pellerin, Olivier Schwartz, Caroline Demeret, Kuang-Yu Chen, Arnaud Fontanet, Lucie Kuhmel, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Sorbonne Université (SU), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Direction de la recherche médicale de l'Institut Pasteur, Centre Médical de l'Institut Pasteur (CMIP), Découverte de pathogènes – Pathogen discovery, Biologie des ARN et virus influenza - RNA Biology of Influenza Virus, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Université Paris Cité (UPCité), Etablissement Français du Sang [La Plaine Saint-Denis] (EFS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Modélisation mathématique des maladies infectieuses - Mathematical modelling of Infectious Diseases, École nationale vétérinaire - Alfort (ENVA), Funding: Institut Pasteur, CNRS, Université de Paris, Santé publique France, Labex IBEID (ANR-10-LABX-62-IBEID), REACTing, EU grant Recover, INCEPTION project (PIA/ANR-16-CONV-0005)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Virus et Immunité - Virus and immunity, Université de Paris (UP), École nationale vétérinaire d'Alfort (ENVA), demeret, caroline, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID, Rapid European COVID-19 Emergency Response research - RECOVER - - H2020-SC1-PHE-CORONAVIRUS-20202020-02-14 - 2022-02-13 - 101003589 - VALID, Centre Médical de l'Institut Pasteur, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0303 health sciences, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, [SDV]Life Sciences [q-bio], Attack rate, Ageusia, Disease cluster, Confidence interval, 3. Good health, Herd immunity, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Internal medicine, Case fatality rate, medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 030212 general & internal medicine, medicine.symptom, business, 030304 developmental biology, Cohort study
Abstract: SummaryBackgroundThe Oise department in France has been heavily affected by COVID-19 in early 2020.MethodsBetween 30 March and 4 April 2020, we conducted a retrospective closed cohort study among pupils, their parents and siblings, as well as teachers and non-teaching staff of a high-school located in Oise. Participants completed a questionnaire that covered history of fever and/or respiratory symptoms since 13 January 2020 and had blood tested for the presence of anti-SARS-CoV-2 antibodies. The infection attack rate (IAR) was defined as the proportion of participants with confirmed SARS-CoV-2 infection based on antibody detection. Blood samples from two blood donor centres collected between 23 and 27 March 2020 in the Oise department were also tested for presence of anti-SARS-CoV-2 antibodies.FindingsOf the 661 participants (median age: 37 years), 171 participants had anti-SARS-CoV-2 antibodies. The overall IAR was 25.9% (95% confidence interval (CI) = 22.6-29.4), and the infection fatality rate was 0% (one-sided 97.5% CI = 0 - 2.1). Nine of the ten participants hospitalised since mid-January were in the infected group, giving a hospitalisation rate of 5.3% (95% CI = 2.4 –9.8). Anosmia and ageusia had high positive predictive values for SARS-CoV-2 infection (84.7% and 88.1%, respectively). Smokers had a lower IAR compared to non-smokers (7.2% versus 28.0%, P InterpretationThe relatively low IAR observed in an area where SARS-CoV-2 actively circulated weeks before confinement measures indicates that establishing herd immunity will take time, and that lifting these measures in France will be long and complex.FundingInstitut Pasteur, CNRS, Université de Paris, Santé publique France, Labex IBEID (ANR-10-LABX-62-IBEID), REACTing, EU grant Recover, INCEPTION project (PIA/ANR-16-CONV-0005).Research in contextEvidence before the studyThe first COVID-19 cases in France were reported on 24 January 2020. Substantial transmission has occurred since then, with the Oise department, north of Paris, one of the heaviest affected areas in the early stages of the epidemic in France. As of 13 April 2020, 98,076 cases had been diagnosed in France, including 5,379 deaths.Epidemiological and clinical characteristics of patients with COVID-19 have been widely reported, but this has largely been centred on cases requiring medical care. What remains unclear at this stage is the extent to which SARS-CoV-2 infections may be asymptomatic or present as subclinical, non-specific symptoms. While extensive contact tracing has identified asymptomatic infections using RT-PCR testing, serologic detection of anti-SARS-CoV-2 antibodies is needed to determine the real infection attack rate and the proportion of all infections that are asymptomatic or subclinical.Added value of this studyUsing a combination of serologic assays with high sensitivity and specificity for anti-SARS-CoV-2 antibodies, we conducted a retrospective closed cohort study. In a high school linked to a cluster of COVID-19 in the Oise department, we showed an overall infection attack rate (IAR) of 40.9% in the high school group, and 10.9% in parents and siblings of the pupils. The proportion of infected individuals who had no symptoms during the study period was 17.0%.Implications of all of the available evidenceThe relatively low IAR in this area where SARS-CoV-2 actively circulated before confinement measures were introduced indicates that establishing herd immunity will take time, and that the lifting of these measures in France will be long and complex.
Published: 2021

33. Influenza A virus co-opts ERI1 exonuclease bound to histone mRNA to promote viral transcription

Author: Cyril Barbezange, Sylvie van der Werf, Yves Jacob, Caroline Demeret, Elise Biquand, Natalia Pietrosemoli, Marwah Karim, Marion Declercq, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), European Union Seventh Framework Program (FP7/2007–2013) [278433-PREDEMICS: Preparedness, Prediction and Prevention of Emerging Zoonotic Viruses with Pandemic Potential using Multidisciplinary Approaches], LabEx Integrative Biology of Emerging Infectious Diseases [10-LABX-0062], Ministère de l’Education Nationale, de la Recherche et de Technologie [PhD fellowships from Université Paris Diderot/Université de Paris to M.D. and E.B.], Fondation pour la Recherche Médicale [Programme Fin de thèse FDT201805005278 to M.D.], Marie Skłodowska-Curie European Union Horizon 2020 research and innovation program [665850 to M.K.]. Funding for open access charge: Unité Génétique Moléculaire des Virus à ARN, UMR3569 CNRS, Université de Paris, Département de Virologie, Institut Pasteur, Paris, France., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 278433,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,PREDEMICS(2011), European Project: 665850,H2020,H2020-MSCA-COFUND-2014,INSPIRE(2015), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Transcription, Genetic, AcademicSubjects/SCI00010, RNA Stability, viruses, [SDV]Life Sciences [q-bio], Virus Replication, medicine.disease_cause, Histones, Transcription (biology), Exoribonuclease, MESH: RNA, Small Interfering, Influenza A virus, RNA, Small Interfering, Ribonucleoprotein, SLBP, MESH: Histones, 0303 health sciences, MESH: Influenza, Human, 030302 biochemistry & molecular biology, Nuclear Proteins, MESH: RNA Stability, 3. Good health, Cell biology, Ribonucleoproteins, MESH: RNA, Viral, Host-Pathogen Interactions, MESH: Exoribonucleases, RNA, Viral, MESH: mRNA Cleavage and Polyadenylation Factors, Exonuclease, MESH: Influenza A virus, Biology, Cell Line, Viral Proteins, 03 medical and health sciences, Influenza, Human, Genetics, medicine, Humans, RNA, Messenger, Molecular Biology, 030304 developmental biology, MESH: RNA, Messenger, mRNA Cleavage and Polyadenylation Factors, Messenger RNA, MESH: Humans, MESH: Transcription, Genetic, MESH: Host-Pathogen Interactions, MESH: Virus Replication, RNA, MESH: Viral Proteins, MESH: Cell Line, MESH: Ribonucleoproteins, Exoribonucleases, biology.protein, MESH: Nuclear Proteins
Abstract: Cellular exonucleases involved in the processes that regulate RNA stability and quality control have been shown to restrict or to promote the multiplication cycle of numerous RNA viruses. Influenza A viruses are major human pathogens that are responsible for seasonal epidemics, but the interplay between viral proteins and cellular exonucleases has never been specifically studied. Here, using a stringent interactomics screening strategy and an siRNA-silencing approach, we identified eight cellular factors among a set of 75 cellular proteins carrying exo(ribo)nuclease activities or involved in RNA decay processes that support influenza A virus multiplication. We show that the exoribonuclease ERI1 interacts with the PB2, PB1 and NP components of the viral ribonucleoproteins and is required for viral mRNA transcription. More specifically, we demonstrate that the protein-protein interaction is RNA dependent and that both the RNA binding and exonuclease activities of ERI1 are required to promote influenza A virus transcription. Finally, we provide evidence that during infection, the SLBP protein and histone mRNAs co-purify with vRNPs alongside ERI1, indicating that ERI1 is most probably recruited when it is present in the histone pre-mRNA processing complex in the nucleus.
Published: 2020
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34. A SARS-CoV-2 – host proximity interactome

Author: Anne-Claude Gingras, James D.R. Knight, Brian Raught, Zhen-Yuan Lin, Payman Samavarchi-Tehrani, Hala Abdouni, Caroline Demeret, Yves Jacob, Brett Larsen, Christopher D. Go, Audrey Astori, Cassandra J. Wong, Jennifer J. Knapp, Jonathan St-Germain, Reuben Samson, Patricia Cassonnet, Frederick P. Roth, Dae-Kyum Kim, Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], Princess Margaret Cancer Centre [Toronto, Canada], University of Toronto, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This project was generously funded by a Fast Grant from the Thistledown Foundation (Canada) to BR,FPR and ACG. This work was also supported by a Canadian Institutes of Health Research FoundationGrant (CIHR FDN 143301 to ACG), and a Natural Sciences and Engineering Research Council ofCanada (NSERC, RGPIN-2014-06434 to ACG). Proteomics work was performed at the NetworkBiology Collaborative Centre at the Lunenfeld-Tanenbaum Research Institute, a facility supported byCanada Foundation for Innovation funding, by the Government of Ontario and by Genome Canadaand Ontario Genomics (OGI-139). Work in the BR lab was also supported by the Canada Foundationfor Innovation (CFI), and The Princess Margaret Cancer Foundation. ACG is the Canada ResearchChair (Tier 1) in Functional Proteomics., and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: G3BP1, stress granules, [SDV]Life Sciences [q-bio], viruses, nucleocapsid, Context (language use), Computational biology, Biology, Proteomics, Interactome, Protein–protein interaction, 03 medical and health sciences, proteomics, 0302 clinical medicine, Viral life cycle, BioID, mass spectrometry, 030304 developmental biology, 0303 health sciences, SARS-CoV-2, Viral replication, Biotinylation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Proteome, 030217 neurology & neurosurgery, proximity interactome
Abstract: Posté sur BioRxiv le 4 septembre 2020 https://www.biorxiv.org/content/10.1101/2020.09.03.282103v1.article-info; Viral replication is dependent on interactions between viral polypeptides and host proteins. Identifying virus-host protein interactions can thus uncover unique opportunities for interfering with the virus life cycle via novel drug compounds or drug repurposing. Importantly, many viral-host protein interactions take place at intracellular membranes and poorly soluble organelles, which are difficult to profile using classical biochemical purification approaches. Applying proximity-dependent biotinylation (BioID) with the fast-acting miniTurbo enzyme to 27 SARS-CoV-2 proteins in a lung adenocarcinoma cell line (A549), we detected 7810 proximity interactions (7382 of which are new for SARS-CoV-2) with 2242 host proteins (results available at covid19interactome.org). These results complement and dramatically expand upon recent affinity purification-based studies identifying stable host-virus protein complexes, and offer an unparalleled view of membrane-associated processes critical for viral production. Host cell organellar markers were also subjected to BioID in parallel, allowing us to propose modes of action for several viral proteins in the context of host proteome remodelling. In summary, our dataset identifies numerous high confidence proximity partners for SARS-CoV-2 viral proteins, and describes potential mechanisms for their effects on specific host cell functions.
Published: 2020
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35. A Comprehensive, Flexible Collection of SARS-CoV-2 Coding Regions

Author: Hunsang Lee, Dayag Sheykhkarimli, Caroline Demeret, Payman Samavarchi-Tehrani, Hala Abdouni, Mikko Taipale, Patricia Cassonnet, Sylvie van der Werf, Roujia Li, Oxana Pogoutse, Anne-Claude Gingras, Yves Jacob, Brian Raught, Jennifer J. Knapp, Da Kuang, Ashyad Rayhan, Etienne Coyaud, Dae-Kyum Kim, Frederick P. Roth, Aditya Chawla, Donnelly Centre [Toronto, ON, Canada], University of Toronto, Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192 (PRISM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Princess Margaret Cancer Centre [Toronto, Canada], This work was supported by a Canadian Institutes for Health ResearchFoundation Grant (F.P.R.), the Canada Excellence ResearchChairs Program (F.P.R.), the Thistledown Foundation (B.R., F.P.R.and A.-C.G.), the LabEx Integrative Biology of Emerging InfectiousDiseases (10-LABX-0062, Y.J.) and Platform for European PreparednessAgainst (Re-)emerging Epidemics, EU (602525, Y.J.)., ANR-10-LABX-0062/10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Canadian Institute for Advanced Research (CIFAR), This work was supported by a Canadian Institutes for Health Research Foundation Grant (F.P.R.), the Canada Excellence Research Chairs Program (F.P.R.), the Thistledown Foundation (B.R., F.P.R. and A.-C.G.), the LabEx Integrative Biology of Emerging Infectious Diseases (10-LABX-0062, Y.J.) and Platform for European Preparedness Against (Re-)emerging Epidemics, EU (602525, Y.J.), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), INSERM, Université de Lille, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CASSONNET, Patricia, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, and Platform foR European Preparedness Against (Re-)emerging Epidemics - PREPARE - - EC:FP7:HEALTH2014-02-01 - 2019-01-31 - 602525 - VALID
Subjects: SARS-CoV-2, coding sequence collection, Gateway-compatible, TEV (tobacco etch virus) sequence, [SDV]Life Sciences [q-bio], viruses, Potyvirus, QH426-470, medicine.disease_cause, 0302 clinical medicine, Pandemic, Coding region, Cloning, Molecular, skin and connective tissue diseases, Genetics (clinical), Coronavirus, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, virus diseases, [SDV] Life Sciences [q-bio], [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Coronavirus Infections, Plasmids, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, Computational biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Investigations, 03 medical and health sciences, Betacoronavirus, Open Reading Frames, Viral life cycle, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Escherichia coli, Genetics, Humans, Molecular Biology, Pandemics, 030304 developmental biology, fungi, COVID-19, body regions, 030217 neurology & neurosurgery, Coding (social sciences)
Abstract: The world is facing a global pandemic of COVID-19 caused by the SARS-CoV-2 coronavirus. Here we describe a collection of codon-optimized coding sequences for SARS-CoV-2 cloned into Gateway-compatible entry vectors, which enable rapid transfer into a variety of expression and tagging vectors. The collection is freely available. We hope that widespread availability of this SARS-CoV-2 resource will enable many subsequent molecular studies to better understand the viral life cycle and how to block it.
Published: 2020
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36. A Flexible Genome-Scale SARS-CoV-2 Clone Resource

Author: Oxana Pogoutse, Caroline Demeret, Jennifer J. Knapp, Kuang D, Dayag Sheykhkarimli, Yves Jacob, Anne-Claude Gingras, Hala Abdouni, Payman Samavarchi-Tehrani, Patricia Cassonnet, Mikko Taipale, Brian Raught, Frederick P. Roth, van der Werf S, Etienne Coyaud, Dae-Kyum Kim, Lee H, Aditya Chawla, and Ashyad Rayhan
Subjects: Resource (biology), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), viruses, Clone (cell biology), Genome scale, other, virus diseases, Computational biology, Biology, 3. Good health
Abstract: The world is facing a major health crisis, the global pandemic of COVID-19 caused by the SARS-CoV-2 coronavirus, for which no approved antiviral agents or vaccines are currently available. Here we describe a collection of codon-optimized coding sequences for SARS-CoV-2 cloned into Gateway-compatible entry vectors, which enable rapid transfer into a variety of expression and tagging vectors. The collection is freely available via Addgene. We hope that widespread availability of this SARS-CoV-2 resource will enable many subsequent molecular studies to better understand the viral life cycle and how to block it.
Published: 2020

37. SARS-CoV-2 infection in primary schools in northern France: A retrospective cohort study in an area of high transmission

Author: Yoann Madec, Pierre Charneau, Bruno Hoen, François Anna, Isabelle Cailleau, Marie-Noëlle Ungeheuer, Caroline Demeret, Lucie Kuhmel, Ludivine Grzelak, Laura Tondeur, Arnaud Fontanet, Olivier Schwartz, Rebecca Grant, Timothée Bruel, Isabelle Staropoli, Charlotte Renaudat, Sandrine Fernandes Pellerin, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Direction de la recherche médicale de l'Institut Pasteur, Institut Pasteur [Paris], Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Centre Médical de l'Institut Pasteur (CMIP), Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris]-TheraVectys, Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), The study was funded by Institut Pasteur, and several laboratories participating in the study receive funding from the Labex IBEID (ANR-10-LABX-62-IBEID), REACTing and the INCEPTION project (PIA/ANR-16-CONV-0005) for studies focusing on emerging viruses. OS lab is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro- Immuno' ANR-14-CE14-0015-01 and the Gilead HIV cure program. LG is supported by the French Ministry of Higher Education, Research and Innovation., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), Centre Médical de l'Institut Pasteur, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-TheraVectys, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: business.industry, Transmission (medicine), [SDV]Life Sciences [q-bio], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), education, Attack rate, School setting, Retrospective cohort study, Familial clustering, Asymptomatic, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, High transmission, Medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 030212 general & internal medicine, medicine.symptom, business, Demography
Abstract: BackgroundThe extent of SARS-CoV-2 transmission among pupils in primary schools and their families is unknown.MethodsBetween 28-30 April 2020, a retrospective cohort study was conducted among pupils, their parents and relatives, and staff of primary schools exposed to SARS-CoV-2 in February and March 2020 in a city north of Paris, France. Participants completed a questionnaire that covered sociodemographic information and history of recent symptoms. A blood sample was tested for the presence of anti-SARS-CoV-2 antibodies using a flow-cytometry-based assay.ResultsThe infection attack rate (IAR) was 45/510 (8.8%), 3/42 (7.1%), 1/28 (3.6%), 76/641 (11.9%) and 14/119 (11.8%) among primary school pupils, teachers, non-teaching staff, parents, and relatives, respectively (P = 0.29). Prior to school closure on February 14, three SARS-CoV-2 infected pupils attended three separate schools with no secondary cases in the following 14 days among pupils, teachers and non-teaching staff of the same schools. Familial clustering of cases was documented by the high proportion of antibodies among parents and relatives of infected pupils (36/59 = 61.0% and 4/9 = 44.4%, respectively). In children, disease manifestations were mild, and 24/58 (41.4%) of infected children were asymptomatic.InterpretationIn young children, SARS-CoV-2 infection was largely mild or asymptomatic and there was no evidence of onwards transmission from children in the school setting.
Published: 2020
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38. Serological signatures of SARS-CoV-2 infection: Implications for antibody-based diagnostics

Author: François Dejardin, Caroline Demeret, Narimane Nekkab, Charlotte Cockram, Michael T. White, Rhea J. Longley, Annalisa Meola, Marija Backovic, Sarah H. Merkling, Stéphane Petres, Jérôme De Seze, Ivo Mueller, Solen Kernéis, Samira Fafi-Kremer, Benjamin Terrier, Stéphane Pelleau, Jason Rosado, Malaria : parasites et hôtes - Malaria : parasites and hosts, Institut Pasteur [Paris], Régulation spatiale des Génomes - Spatial Regulation of Genomes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Interactions Virus-Insectes - Insect-Virus Interactions (IVI), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Virologie Structurale, Equipe mobile d'infectiologie, CHU Necker - Enfants Malades [AP-HP], Epidémiologie et modélisation de la résistance aux antimicrobiens - Epidemiology and modelling of bacterial escape to antimicrobials, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Référence Maladies auto-immunes Systémiques Rares [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie [Strasbourg], CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, The Walter and Eliza Hall Institute of Medical Research (WEHI), Santé publique : épidémiologie & sciences de l'information biomédicale (ED 393), Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Virologie Structurale - Structural Virology, Epidémiologie et modélisation de la résistance aux antimicrobiens - Epidemiology and modelling of bacterial escape to antimicrobials (EMAE), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Melbourne, This work was supported by the European Research Council (MultiSeroSurv ERC Starting Grant, MW), l’Agence Nationale de la Recherche and Fondation pour la Recherche Médicale (CorPopImm, MW), and the Institut Pasteur International Network (CoronaSeroSurv, MW). JR was supported by the Pasteur Paris University (PPU) International PhD Program, Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Michael, White, Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Serology, Peak response, 03 medical and health sciences, 0302 clinical medicine, Antigen, Medicine, Multiplex, 030212 general & internal medicine, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, 030304 developmental biology, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, biology, business.industry, Serum samples, Confidence interval, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Antibody, business
Abstract: BackgroundInfection with SARS-CoV-2 induces an antibody response targeting multiple antigens that changes over time. This complexity presents challenges and opportunities for serological diagnostics.MethodsA multiplex serological assay was developed to measure IgG and IgM antibody responses to seven SARS-CoV-2 spike or nucleoprotein antigens, two antigens for the nucleoproteins of the 229E and NL63 seasonal coronaviruses, and three non-coronavirus antigens. Antibodies were measured in serum samples from patients in French hospitals with RT-qPCR confirmed SARS-CoV-2 infection (n= 259), and negative control serum samples collected before the start of the SARS-CoV-2 epidemic (n= 335). A random forests algorithm was trained with the multiplex data to classify individuals with previous SARS-CoV-2 infection. A mathematical model of antibody kinetics informed by prior information from other coronaviruses was used to estimate time-varying antibody responses and assess the potential sensitivity and classification performance of serological diagnostics during the first year following symptom onset. A statistical estimator is presented that can provide estimates of seroprevalence in very low transmission settings.ResultsIgG antibody responses to trimeric Spike protein identified individuals with previous RT-qPCR confirmed SARS-CoV-2 infection with 91.6% sensitivity (95% confidence interval (CI); 87.5%, 94.5%) and 99.1% specificity (95% CI; 97.4%, 99.7%). Using a serological signature of IgG and IgM to multiple antigens, it was possible to identify infected individuals with 98.8% sensitivity (95% CI; 96.5%, 99.6%) and 99.3% specificity (95% CI; 97.6%, 99.8%). Informed by prior data from other coronaviruses, we estimate that one year following infection a monoplex assay with optimal anti-StriIgG cutoff has 88.7% sensitivity (95% CI: 63.4%, 97.4%), and that a multiplex assay can increase sensitivity to 96.4% (95% CI: 80.9%, 100.0%). When applied to population-level serological surveys, statistical analysis of multiplex data allows estimation of seroprevalence levels less than 1%, below the false positivity rate of many other assays.ConclusionSerological signatures based on antibody responses to multiple antigens can provide accurate and robust serological classification of individuals with previous SARS-CoV-2 infection. This provides potential solutions to two pressing challenges for SARS-CoV-2 serological surveillance: classifying individuals who were infected greater than six months ago, and measuring seroprevalence in serological surveys in very low transmission settings.
Published: 2020

39. A Flexible Genome-Scale Resource of SARS-CoV-2 Coding Sequence Clones

Author: Caroline Demeret, Etienne Coyaud, Patricia Cassonnet, Da Kuang, Ashyad Rayhan, Dae-Kyum Kim, Frederick P. Roth, Payman Samavarchi-Tehrani, Sylvie van der Werf, Hala Abdouni, Anne-Claude Gingras, Dayag Sheykhkarimli, Jennifer J. Knapp, Brian Raught, and Yves Jacob
Subjects: 0303 health sciences, Resource (biology), Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), viruses, 030302 biochemistry & molecular biology, Genome scale, other, virus diseases, Computational biology, Biology, medicine.disease_cause, 3. Good health, 03 medical and health sciences, medicine, Coding region, 030304 developmental biology, Coronavirus
Abstract: The world is facing a major health crisis, the global pandemic of COVID-19 caused by the SARS-CoV-2 coronavirus, for which no approved antiviral agents or vaccines are currently available. Here we describe a collection of codon-optimized coding sequences for SARS-CoV-2 cloned into Gateway-compatible entry vectors, which enable rapid transfer into a variety of expression and tagging vectors. The collection is freely available via Addgene. We hope that widespread availability of this SARS-CoV-2 resource will enable many subsequent molecular studies to better understand the viral life cycle and how to block it.
Published: 2020

40. SARS-CoV-2 serological analysis of COVID-19 hospitalized patients, pauci-symptomatic individuals and blood donors

Author: Lucie Le Fevre, Diane Descamps, Sylvie van der Werf, Nicolas Escriou, Delphine Planas, Olivier Schwartz, Flora Donati, Cyril Planchais, Rémy Robinot, Isabelle Staropoli, Bernadette Crescenzo, Bruno Hoen, Mireille Nowakowski, Marion Gransagne, Mélanie Albert, Jérémy Dufloo, Marc Eloit, Stéphane Petres, Camille Besombes, Ludivine Grzelak, Yazdan Yazdanpanah, Hugo Mouquet, Sarah Temmam, Arnaud Fontanet, Pierre Charneau, Marija Backovic, Vincent Enouf, Pascal Morel, Françoise Porrot, Quentin Le Hingrat, Audrey Lemaitre, Timothée Bruel, Philippe Souque, Maxime Chazal, Guillaume Mellon, Laura Tondeur, Anabelle Pourbaix, Simon Rolland, Félix A. Rey, Christèle Huon, Julian Buchrieser, Sylvie Behillil, Marie-Noëlle Ungeheuer, François Anna, Maaran Michael Rajah, Lila Bouadma, Florence Guivel, Jacques Bellalou, Marie-Aude Creach, Caroline Demeret, and Kuang-Yu Chen
Subjects: 0303 health sciences, education.field_of_study, biology, 030306 microbiology, business.industry, Population, Antibody titer, Virology, Asymptomatic, 3. Good health, Serology, 03 medical and health sciences, Antigen, biology.protein, Medicine, Seroprevalence, Antibody, Seroconversion, medicine.symptom, education, business, 030304 developmental biology
Abstract: It is of paramount importance to evaluate the prevalence of both asymptomatic and symptomatic cases of SARS-CoV-2 infection and their antibody response profile. Here, we performed a pilot study to assess the levels of anti-SARS-CoV-2 antibodies in samples taken from 491 pre-epidemic individuals, 51 patients from Hôpital Bichat (Paris), 209 pauci-symptomatic individuals in the French Oise region and 200 contemporary Oise blood donors. Two in-house ELISA assays, that recognize the full-length nucleoprotein (N) or trimeric Spike (S) ectodomain were implemented. We also developed two novel assays: the S-Flow assay, which is based on the recognition of S at the cell surface by flow-cytometry, and the LIPS assay that recognizes diverse antigens (including S1 or N C-terminal domain) by immunoprecipitation. Overall, the results obtained with the four assays were similar, with differences in sensitivity that can be attributed to the technique and the antigen in use. High antibody titers were associated with neutralisation activity, assessed using infectious SARS-CoV-2 or lentiviral-S pseudotypes. In hospitalized patients, seroconversion and neutralisation occurred on 5-14 days post symptom onset, confirming previous studies. Seropositivity was detected in 29% of pauci-symptomatic individuals within 15 days post-symptoms and 3 % of blood of healthy donors collected in the area of a cluster of COVID cases. Altogether, our assays allow for a broad evaluation of SARS-CoV2 seroprevalence and antibody profiling in different population subsets.
Published: 2020
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41. Nonproteolytic K29-Linked Ubiquitination of the PB2 Replication Protein of Influenza A Viruses by Proviral Cullin 4-Based E3 Ligases

Author: Marion Declercq, Caroline Demeret, Yves Jacob, Sylvie van der Werf, Marwah Karim, Elise Biquand, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), M.K. is part of the INSPIRE program funded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 665850. E.B. and M.D. were recipients of a MENRT PhD fellowship from Université Paris Diderot/Université de Paris. This work was supported by the Institut Pasteur PTR no. 546, EU FP7 PREDEMICS (grant agreement 278433), and the LabEx Integrative Biology of Emerging Infectious Diseases (grant 10-LABX-0062)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 665850,H2020,H2020-MSCA-COFUND-2014,INSPIRE(2015), European Project: 278433,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,PREDEMICS(2011), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: nonproteolytic ubiquitination, Ubiquitin-Protein Ligases, viruses, [SDV]Life Sciences [q-bio], Lysine, medicine.disease_cause, Virus Replication, ubiquitination, Microbiology, influenza virus, Host-Microbe Biology, 03 medical and health sciences, DDB1, Viral Proteins, 0302 clinical medicine, Ubiquitin, Proviruses, Transcription (biology), Virology, Influenza A virus, medicine, PB2 replication protein, Humans, cullin-based E3 ligases, 030304 developmental biology, 0303 health sciences, biology, virus diseases, Cullin Proteins, RNA-Dependent RNA Polymerase, QR1-502, 3. Good health, Ubiquitin ligase, Cell biology, K29-linked ubiquitination, HEK293 Cells, Viral replication, post-translational modification, A549 Cells, 030220 oncology & carcinogenesis, Host-Pathogen Interactions, biology.protein, Protein Processing, Post-Translational, Cullin, Research Article
Abstract: Successful infection by influenza A virus, a pathogen of major public health importance, involves fine regulation of the multiple functions of the viral proteins, which often relies on post-translational modifications (PTMs). The PB2 protein of influenza A viruses is essential for viral replication and a key determinant of host range. While PTMs of PB2 inducing its degradation have been identified, here we show that PB2 undergoes a regulating PTM signaling detected during infection, based on an atypical K29-linked ubiquitination and mediated by two multicomponent E3 ubiquitin ligases. Recombinant viruses impaired for CRL4-mediated ubiquitination are attenuated, indicating that ubiquitination of PB2 is necessary for an optimal influenza A virus infection. The CRL4 E3 ligases are required for normal viral cycle progression and for maximal virion production. Consequently, they represent potential candidate host factors for antiviral targets., The multifunctional nature of viral proteins is essentially driven by posttranslational modifications (PTMs) and is key for the successful outcome of infection. For influenza A viruses (IAVs), a composite pattern of PTMs regulates the activity of viral proteins. However, almost none are known that target the PB2 replication protein, except for inducing its degradation. We show here that PB2 undergoes a nonproteolytic ubiquitination during infection. We identified E3 ubiquitin ligases catalyzing this ubiquitination as two multicomponent RING-E3 ligases based on cullin 4 (CRL4s), which are both contributing to the levels of ubiquitinated forms of PB2 in infected cells. The CRL4 E3 ligase activity is required for the normal progression of the viral cycle and for maximal virion production, indicating that the CRL4s mediate a ubiquitin signaling that promotes infection. The CRL4s are recruiting PB2 through an unconventional bimodal interaction with both the DDB1 adaptor and DCAF substrate receptors. While able to bind to PB2 when engaged in the viral polymerase complex, the CRL4 factors do not alter transcription and replication of the viral segments during infection. CRL4 ligases catalyze different patterns of lysine ubiquitination on PB2. Recombinant viruses mutated in the targeted lysines showed attenuated viral production, suggesting that CRL4-mediated ubiquitination of PB2 contributes to IAV infection. We identified K29-linked ubiquitin chains as main components of the nonproteolytic PB2 ubiquitination mediated by the CRL4s, providing the first example of the role of this atypical ubiquitin linkage in the regulation of a viral infection.
Published: 2020
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42. Structure resolution of the trimeric RNA-dependent RNA polymerase of influenza viruses: impact on our understanding of polymerase interactions with host and viral factors

Author: Élise, Biquand and Caroline, Demeret
Abstract: Influenza viruses are segmented negative-sense RNA viruses whose RNA dependant RNA polymerase (RdRp) multiple activities multiple activities are central for the viral life cycle. The RdRp is composed of three subunits, PB1, PB2 and PA. It binds to the extremities of each vRNA segments encapsidated with multiple copies of the Nucleoprotein (NP), altogether constituting the viral ribonucleoprotein (vRNP). The RdRp performs both vRNA transcription and replication in the context of vRNP in the nuclei of infected cells. The temporal regulation of RdRp-associated activities is essential for the successful completion of the virus life cycle, but its understanding has been limited by the lack of structural information about the polymerase complex. The atomic-resolution of polymerase complexes from influenza virus type A, type B and type C came out in the past two years.We compile here the data provided by the near-concomitant resolution of several influenza polymerase crystal structures. We will highlight how structural information can contribute to our understanding of the interactions between the RdRp and viral or host factors.
Published: 2020

43. Mapping the interactome of HPV E6 and E7 oncoproteins with the ubiquitin-proteasome system

Author: Louis Jones, Katia Zanier, Elise Biquand, Juline Poirson, Gilles Travé, Yves Nominé, Caroline Demeret, Marie Laure Straub, Sylvie van der Werf, Patricia Cassonnet, Murielle Masson, Yves Jacob, Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported by the CNRS, the University of Strasbourg, the Ligue Nationale Contre le Cancer (CCIR‐GE), ANR (INFECT‐ERA, HPV‐motiva project), Alsace Contre le Cancer. JP was a recipient of a PhD fellowship of the Ligue Nationale Contre le Cancer and Alsace Contre le Cancer. EB was a recipient of a MENRT PhD fellowship., We thank the Center for Cancer Systems Biology (CCSB) at the Dana‐Farber Cancer Institute (Boston, MA, USA) for providing us with ORFs. We thank Katja Luck for helpful discussion and Noëlla Mukobo for technical assistance., ANR-15-IFEC-0004,HPV-MOTIVA,HUMAN PAPILLOMAVIRUS INFECTION- FROM MOLECULES TO TISSUES TO PREVENTION(2015), ANR-14-IFEC-0006,BactInfectERA,Bacterial interaction with the microvasculature, a target for therapeutic intervention during septicaemia(2014), demeret, caroline, HUMAN PAPILLOMAVIRUS INFECTION- FROM MOLECULES TO TISSUES TO PREVENTION - - HPV-MOTIVA2015 - ANR-15-IFEC-0004 - Infect-ERA - VALID, Recherche transnationale sur les maladies infectieuses humaines - Bacterial interaction with the microvasculature, a target for therapeutic intervention during septicaemia - - BactInfectERA2014 - ANR-14-IFEC-0006 - IFEC - VALID, Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Papillomavirus E7 Proteins, [SDV]Life Sciences [q-bio], Aucun, Apoptosis, Ubiquitin-conjugating enzyme, Virus Replication, Biochemistry, Deubiquitinating enzyme, Ubiquitin, Genes, Reporter, Protein Interaction Mapping, Luciferases, ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Genetics, Human papillomavirus 16, biology, Ubiquitin-Protein Ligase Complexes, 3. Good health, Ubiquitin ligase, Cell biology, [SDV] Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Host-Pathogen Interactions, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Ubiquitin-Specific Proteases, Cullin, Protein Binding, Deubiquitination, Proteasome Endopeptidase Complex, HPV, Ubiquitin-Protein Ligases, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, ubiquitination, 03 medical and health sciences, Peptide Library, Humans, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Biology, Adaptor Proteins, Signal Transducing, Computational Biology, Proteins, Molecular Sequence Annotation, Oncogene Proteins, Viral, Cell Biology, Protein ubiquitination, Repressor Proteins, 030104 developmental biology, Gene Expression Regulation, interactomic, Proteasome, biology.protein, Carrier Proteins, protein complementation assay
Abstract: International audience; Protein ubiquitination and its reverse reaction, deubiquitination, regulate protein stability, protein binding activity, and their subcellular localization. These reactions are catalyzed by the enzymes E1, E2, and E3 ubiquitin (Ub) ligases and deubiquitinases (DUBs). The Ub-proteasome system (UPS) is targeted by viruses for the sake of their replication and to escape host immune response. To identify novel partners of human papillomavirus 16 (HPV16) E6 and E7 proteins, we assembled and screened a library of 590 cDNAs related to the UPS by using the Gaussia princeps luciferase protein complementation assay. HPV16 E6 was found to bind to the homology to E6AP C terminus-type Ub ligase (E6AP), three really interesting new gene (RING)-type Ub ligases (MGRN1, LNX3, LNX4), and the DUB Ub-specific protease 15 (USP15). Except for E6AP, the binding of UPS factors did not require the LxxLL-binding pocket of HPV16 E6. LNX3 bound preferentially to all high-risk mucosal HPV E6 tested, whereas LNX4 bound specifically to HPV16 E6. HPV16 E7 was found to bind to several broad-complex tramtrack and bric-a-brac domain-containing proteins (such as TNFAIP1/KCTD13) that are potential substrate adaptors of Cullin 3-RING Ub ligases, to RING-type Ub ligases implicated in innate immunity (RNF135, TRIM32, TRAF2, TRAF5), to the substrate adaptor DCAF15 of Cullin 4-RING Ub ligase and to some DUBs (USP29, USP33). The binding to UPS factors did not require the LxCxE motif but rather the C-terminal region of HPV16 E7 protein. The identified UPS factors interacted with most of E7 proteins across different HPV types. This study establishes a strategy for the rapid identification of interactions between host or pathogen proteins and the human ubiquitination system.
Published: 2017
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44. Cluster of COVID-19 in Northern France: A Retrospective Closed Cohort Study

Author: Olivier Schwartz, Yoann Madec, Timothée Bruel, Camille Besombes, Nathalie Jolly, Christèle Huon, Laura Tondeur, Rebecca Grant, Marie-Noëlle Ungeheuer, Sandie Munier, Bruno Hoen, Sylvie van der Werf, Sandrine Fernandes Pellerin, Sarah Temmam, Ludivine Grzelak, Pierre Gallian, Marc Eloit, Isabelle Cailleau, Caroline Demeret, Simon Cauchemez, Kuang-Yu Chen, Arnaud Fontanet, Lucie Kuhmel, Bernadette Crescenzo, and Isabelle Staropoli
Subjects: medicine.medical_specialty, biology, Coronavirus disease 2019 (COVID-19), business.industry, Attack rate, Disease cluster, biology.organism_classification, Herd immunity, Informed consent, Family medicine, Case fatality rate, medicine, business, Sida, Cohort study
Abstract: Background: The Oise department in France has been heavily affected by COVID-19 in early 2020. Methods: Between 30 March and 4 April 2020, we conducted a retrospective closed cohort study among pupils, their parents and siblings, as well as teachers and non-teaching staff of a high-school located in Oise. Participants completed a questionnaire that covered history of fever and/or respiratory symptoms since 13 January 2020 and had blood tested for the presence of anti-SARS-CoV-2 antibodies. The infection attack rate (IAR) was defined as the proportion of participants with confirmed SARS-CoV-2 infection based on antibody detection. Blood samples from two blood donor centres collected between 23 and 27 March 2020 in the Oise department were also tested for presence of anti-SARS-CoV-2 antibodies. Findings: Of the 661 participants (median age: 37 years), 171 participants had anti-SARS-CoV-2 antibodies. The overall IAR was 25.9% (95% confidence interval (CI) = 22.6-29.4), and the infection fatality rate was 0% (one-sided 97.5% CI = 0 - 2.1). Nine of the ten participants hospitalised since mid-January were in the infected group, giving a hospitalisation rate of 5.3% (95% CI = 2.4 –9.8). Anosmia and ageusia had high positive predictive values for SARS-CoV-2 infection (84.7% and 88.1%, respectively). Smokers had a lower IAR compared to non-smokers (7.2% versus 28.0%, P
Published: 2020
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45. Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

Author: Estelle M.N. Laurent, Da Kuang, Frederick P. Roth, Michel Salzet, Sylvie van der Werf, David E. Hill, Caroline Demeret, Dae-Kyum Kim, Oxana Pogoutse, Georgios A. Pavlopoulos, Anne-Claude Gingras, Michael A. Calderwood, Marc Vidal, Hala Abdouni, Patricia Cassonnet, Yves Jacob, Anastassia V. Komarova, Aditya Chawla, Patrick Aloy, Isabelle Fournier, Ashyad Rayhan, Pascal Falter-Braun, Jean-Pascal Gimeno, Ulrich Stelzl, Roujia Li, Etienne Coyaud, Jennifer J. Knapp, Dayag Sheykhkarimli, Marie Duhamel, Payman Samavarchi Tehrani, Yorgos Sofianatos, CASSONNET, Patricia, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institute for Fundamental Biomedical Research [Vari, Greece], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], Dana-Farber Cancer Institute [Boston], Harvard Medical School [Boston] (HMS), Ludwig-Maximilians-Universität München (LMU), Barcelona Institute of Science and Technology (BIST), Karl-Franzens-Universität Graz, The operational costs of this project were supported by the Agence Nationale pour la Recherche (ANR) Flash COVID-19 funding scheme (DARWIN project). E.MN.L. was supported by Métropole Européenne de Lille (France). Y.S. was supported by the Operational Program Competitiveness, Entrepreneurship and Innovation, NSRF 2014-2020, Action code: MIS 5002562, co-financed by Greece and the European Union (European Regional Development Fund) and by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 838018. GAP was supported by the Hellenic Foundation for Research and Innovation (H.F.R.I) under the 'First Call for H.F.R.I Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant' (grant 1855-BOLOGNA). FPR is supported by a Canadian Institutes of Health Research (CIHR) Foundation Grant and the Canada Excellence Research Chairs Program. A.-C.G. holds the Canada Research Chair (Tier 1) in Functional Proteomics. P.A. and P.F.B. were funded by the European Research Council’s Horizon 2020 Research and Innovation Action (Grant Agreement 101003633 - RiPCoN). E.C. was funded by I-Site Lille, Région Hauts-de-France and European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 843052., Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Karl-Franzens-Universität [Graz, Autriche], University of Graz, and ANR-20-COVI-0063,DARWIN,Identification des interactions entre protéines du SARS CoV-2 et les facteurs de la réponse immunitaire innée(2020)
Subjects: [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Innate immune system, [SDV]Life Sciences [q-bio], Computational biology, Biology, Protein kinase R, Interactome, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Membrane protein, Interaction network, Interferon, 030220 oncology & carcinogenesis, Biotinylation, Proteome, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, medicine, 030304 developmental biology, medicine.drug
Abstract: The worldwide SARS-CoV-2 outbreak poses a serious challenge to human societies and economies. SARS-CoV-2 proteins orchestrate complex pathogenic mechanisms that underlie COVID-19 disease. Thus, understanding how viral polypeptides rewire host protein networks enables better-founded therapeutic research. In complement to existing proteomic studies, in this study we define the first proximal interaction network of SARS-CoV-2 proteins, at the whole proteome level in human cells. Applying a proximity-dependent biotinylation (BioID)-based approach greatly expanded the current knowledge by detecting interactions within poorly soluble compartments, transient, and/or of weak affinity in living cells. Our BioID study was complemented by a stringent filtering and uncovered 2,128 unique cellular targets (1,717 not previously associated with SARS-CoV-1 or 2 proteins) connected to the N- and C-ter BioID-tagged 28 SARS-CoV-2 proteins by a total of 5,415 (5,236 new) proximal interactions. In order to facilitate data exploitation, an innovative interactive 3D web interface was developed to allow customized analysis and exploration of the landscape of interactions (accessible at http://www.sars-cov-2-interactome.org/). Interestingly, 342 membrane proteins including interferon and interleukin pathways factors, were associated with specific viral proteins. We uncovered ORF7a and ORF7b protein proximal partners that could be related to anosmia and ageusia symptoms. Moreover, comparing proximal interactomes in basal and infection-mimicking conditions (poly(I:C) treatment) allowed us to detect novel links with major antiviral response pathway components, such as ORF9b with MAVS and ISG20; N with PKR and TARB2; NSP2 with RIG-I and STAT1; NSP16 with PARP9-DTX3L. Altogether, our study provides an unprecedented comprehensive resource for understanding how SARS-CoV-2 proteins orchestrate host proteome remodeling and innate immune response evasion, which can inform development of targeted therapeutic strategies.
Published: 2020

46. Maximizing binary interactome mapping with a minimal number of assays

Author: Sudharshan Rangarajan, Philipp Trepte, Luke Lambourne, Soon Gang Choi, Patricia Cassonnet, Irma Lemmens, Javier De Las Rivas, Tong Hao, Wenting Bian, Marc Vidal, Eloi P. Coutant, Pierre-Olivier Vidalain, David E. Hill, Caroline Demeret, Mélanie Dos Santos, Michael A. Calderwood, Louis Jones, Julien Olivet, Kerstin Spirohn, Sylvie van der Werf, Erich E. Wanker, Jan Tavernier, Yves Jacob, Yves L. Janin, Jean-Claude Twizere, Katja Luck, Dana-Farber Cancer Institute [Boston], Université de Liège, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Harvard Medical School [Boston] (HMS), Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Universiteit Gent = Ghent University [Belgium] (UGENT), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Chimie et Biocatalyse, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Universidad de Salamanca, This work was supported by a Claudia Adams Barr Award to S.G.C., a Fonds de la Recherche Scientifique (F.R.S.-FNRS)-Télévie Grant and a Wallonia-Brussels International (WBI)-World Excellence Fellowship to J.O., NHGRI grants U41HG001715 awarded to M.V., D.E.H. and M.A.C, and P50HG004233 awarded to M.V. We acknowledge the support of Labex IBEID (10-LABX-0062). M.V. is a Chercheur Qualifié Honoraire from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Fonds de la Recherche Scientifique (Fédération Wallonie-Bruxelles), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), Max Delbrück Center for Molecular Medicine [Berlin], and ANR-10-LABX-0062/10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: Proteomics, 0301 basic medicine, Proteome, Computer science, Science, High-throughput screening, Proteomic analysis, General Physics and Astronomy, Binary number, 02 engineering and technology, Computational biology, Genome, Interactome, Article, General Biochemistry, Genetics and Molecular Biology, Protein expression, 03 medical and health sciences, Two-Hybrid System Techniques, Protein Interaction Mapping, Humans, Protein Interaction Maps, lcsh:Science, Databases, Protein, Multidisciplinary, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Proteins, General Chemistry, 021001 nanoscience & nanotechnology, Protein-protein interaction networks, High-Throughput Screening Assays, HEK293 Cells, 030104 developmental biology, Protein–protein interaction networks, lcsh:Q, Biological Assay, Systematic mapping, Function and Dysfunction of the Nervous System, 0210 nano-technology, Completeness (statistics), HeLa Cells
Abstract: © The Author(s) 2019., Complementary assays are required to comprehensively map complex biological entities such as genomes, proteomes and interactome networks. However, how various assays can be optimally combined to approach completeness while maintaining high precision often remains unclear. Here, we propose a framework for binary protein-protein interaction (PPI) mapping based on optimally combining assays and/or assay versions to maximize detection of true positive interactions, while avoiding detection of random protein pairs. We have engineered a novel NanoLuc two-hybrid (N2H) system that integrates 12 different versions, differing by protein expression systems and tagging configurations. The resulting union of N2H versions recovers as many PPIs as 10 distinct assays combined. Thus, to further improve PPI mapping, developing alternative versions of existing assays might be as productive as designing completely new assays. Our findings should be applicable to systematic mapping of other biological landscapes., This work was supported by a Claudia Adams Barr Award to S.G.C., a Fonds de la Recherche Scientifique (F.R.S.- FNRS)-Télévie Grant and a Wallonia-Brussels International (WBI)-World Excellence Fellowship to J.O., NHGRI grants U41HG001715 awarded to M.V., D.E.H. and M.A.C, and P50HG004233 awarded to M.V. We acknowledge the support of Labex IBEID (10- LABX-0062). M.V. is a Chercheur Qualifié Honoraire from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium).
Published: 2019
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47. OTUB1 is a key regulator of RIG-I dependent immune signalling and is targeted for proteasomal degradation by influenza A NS1

Author: Chris Ka Pun Mok, Qi Wen Teo, Sumana Sanyal, Sophie Doak, Caroline Demeret, Leo L.M. Poon, Akhee Sabiha Jahan, Artejan te Velthuis, Raquel Muñoz-Moreno, Elise Biquand, Alex W.H. Chin, Ho Him Wong, Agathe Le Quang, and Adolfo García-Sastre
Subjects: biology, Chemistry, RIG-I, viruses, Regulator, virus diseases, chemical and pharmacologic phenomena, biochemical phenomena, metabolism, and nutrition, medicine.disease_cause, Cell biology, Cytosol, Ubiquitin, OTUB1, Influenza A virus, medicine, biology.protein, Signal transduction, IRF3
Abstract: SummaryDeubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host innate immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, DUBs that regulate this pathway have not been identified. Using a ubiquitin C-terminal electrophile, we profiled DUBs that function during influenza A virus (IAV) infection, and isolated OTUB1 as a key regulator of RIG-I dependent antiviral responses. OTUB1 was interferon-inducible, and interacted with RIG-I, viral PB2 and NS1. Upon infection, OTUB1 relocalised from the nucleus to mitochondrial membranes, and activated the RIG-I signaling complex via hydrolysis of K48 polyubiquitin chains and by forming a repressive complex with UBCH5c. Using a reconstituted system composed of in vitro translated [35S]IRF3, purified RIG-I, mitochondrial membranes and cytosol expressing OTUB1 variants, we recapitulated the mechanism of OTUB1-dependent RIG-I activation. A wide range of IAV NS1 proteins triggered proteasomal degradation of OTUB1, thereby antagonizing the RIG-I signaling cascade and antiviral responses.HighlightsOTUB1 is induced during influenza A virus infections in an IFN-I dependent mannerOTUB1 regulates the RIG-I complex by hydrolysing K48-linked polyubiquitin chains and by sequestering UBCH5c to prevent K48 polyubiquitylationOptimal K63 versus K48 polyubiquitin chain concentrations determine RIG-I activationInfluenza NS1 targets OTUB1 for proteasomal degradation
Published: 2019
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48. MARCH8 Ubiquitinates the Hepatitis C Virus Nonstructural 2 Protein and Mediates Viral Envelopment

Author: Yves Jacob, Sathish Kumar, Fei Xiao, Albert Lu, Rina Barouch-Bentov, Szu-Yuan Pu, Caroline Demeret, Elise Biquand, Stanford Schor, Shirit Einav, Brett D. Lindenbach, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Yale University School of Medicine, This work was supported by grants from Stanford Bio-X Interdisciplinary Initiative Program Award, grant RSG-14-11 0-0 1-MPC from the American Cancer Society, and grant 1U19AI10966201 from the National Institute of Allergy and Infectious Diseases to S.E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Stanford University School of Medicine [Stanford], Stanford University [Stanford], Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Yale School of Medicine [New Haven, Connecticut] (YSM)
Subjects: 0301 basic medicine, hepatitis C virus, assembly, Viral protein, Ubiquitin-Protein Ligases, viruses, MARCH8, Hepacivirus, Viral Nonstructural Proteins, Endoplasmic Reticulum, medicine.disease_cause, Proteomics, ubiquitination, Interactome, Article, General Biochemistry, Genetics and Molecular Biology, ESCRT, 03 medical and health sciences, 0302 clinical medicine, proteomics, Ubiquitin, Cell Line, Tumor, medicine, Humans, lcsh:QH301-705.5, virus-host interactions, chemistry.chemical_classification, DNA ligase, biology, envelopment, intracellular membrane trafficking, virus diseases, Hepatitis C, Virology, 3. Good health, Ubiquitin ligase, HEK293 Cells, 030104 developmental biology, lcsh:Biology (General), Proteasome, chemistry, HCV, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, 030217 neurology & neurosurgery, Signal Transduction
Abstract: SUMMARY The mechanisms that regulate envelopment of HCV and other viruses that bud intracellularly and/or lack late-domain motifs are largely unknown. We reported that K63 polyubiquitination of the HCV nonstructural (NS) 2 protein mediates HRS (ESCRT-0 component) binding and envelopment. Nevertheless, the ubiquitin signaling that governs NS2 ubiquitination remained unknown. Here, we map the NS2 interactome with the ubiquitin proteasome system (UPS) via mammalian cell-based screens. NS2 interacts with E3 ligases, deubiquitinases, and ligase regulators, some of which are candidate proviral or antiviral factors. MARCH8, a RING-finger E3 ligase, catalyzes K63-linked NS2 polyubiquitination in vitro and in HCV-infected cells. MARCH8 is required for infection with HCV, dengue, and Zika viruses and specifically mediates HCV envelopment. Our data reveal regulation of HCV envelopment via ubiquitin signaling and both a viral protein substrate and a ubiquitin K63-linkage of the understudied MARCH8, with potential implications for cell biology, virology, and host-targeted antiviral design., In Brief The mechanisms that regulate intracellular viral envelopment are unknown. Kumar et al. report that MARCH8 catalyzes K63-linked polyubiquitination of the HCV nonstructural 2 protein and subsequently ESCRT recruitment and HCV envelopment. MARCH8 is required for infection with other Flaviviridae family members, thereby representing a potential host target for antiviral strategies., Graphical Abstract
Published: 2019
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49. Towards an 'assayome' for binary interactome mapping

Author: Jan Tavernier, Sylvie van der Werf, Mélanie Dos Santos, Eloi P. Coutant, Erich E. Wanker, Julien Olivet, Luke Lambourne, Philipp Trepte, Marc Vidal, Pierre-Olivier Vidalain, Michael A. Calderwood, Jean-Claude Twizere, Irma Lemmens, Louis Jones, Wenting Bian, Sudharshan Rangarajan, Katja Luck, Javier De Las Rivas, Patricia Cassonnet, Tong Hao, Yves L. Janin, Soon Gang Choi, Kerstin Spirohn, David E. Hill, Caroline Demeret, and Yves Jacob
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Computer science, Completeness (order theory), Proteome, Binary number, Computational biology, Interactome, Genome, 030217 neurology & neurosurgery, Protein expression, 030304 developmental biology
Abstract: Complementary assays are required to comprehensively map complex biological entities such as genomes, proteomes and interactome networks. However, how various assays can be optimally combined to approach completeness while maintaining high precision often remains unclear. Here, we propose the concept of an “assayome” for binary protein-protein interaction (PPI) mapping as an optimal combination of assays and/or assay versions that maximizes detection of true positive interactions, while avoiding detection of random protein pairs. We engineered a novel NanoLuc two-hybrid (N2H) system that integrates 12 different versions differing by protein expression systems and tagging configurations. The resulting N2H assayome recovers as many PPIs as 10 distinct assays combined. Thus, to further improve PPI mapping, developing alternative versions of existing assays might be as productive as designing completely new assays. Our assayome concept should be applicable to systematic mapping of other biological landscapes.
Published: 2019
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50. [Interactions with the ubiquitin system: a prerequisite for influenza virus adaptation to humans?]

Author: Élise, Biquand and Caroline, Demeret
Subjects: Influenza A virus, Ubiquitin, Host-Pathogen Interactions, Influenza, Human, Humans, Adaptation, Physiological
Published: 2018

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