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1. Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2

Author: Manon Venet, Margarida Sa Ribeiro, Elodie Décembre, Alicia Bellomo, Garima Joshi, Célia Nuovo, Marine Villard, David Cluet, Magali Perret, Rémi Pescamona, Helena Paidassi, Thierry Walzer, Omran Allatif, Alexandre Belot, Sophie Trouillet-Assant, Emiliano P. Ricci, and Marlène Dreux
Subjects: Science
Abstract: Plasmacytoid DC (pDC) have been shown to secrete type I IFN and to be involved in controlling replication and spread of some viruses. Here the authors show that in severe SARS-CoV-2 infection pDC function is impaired leading to reduced type I IFN production and possibly lower viral control.
Published: 2023
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2. Immunoprofiling of fresh HAM/TSP blood samples shows altered innate cell responsiveness.

Author: Brenda Rocamonde, Nicolas Futsch, Noemia Orii, Omran Allatif, Augusto Cesar Penalva de Oliveira, Renaud Mahieux, Jorge Casseb, and Hélène Dutartre
Subjects: Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract: The Human T-cell Leukemia Virus-1 (HTLV-1)-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a devastating neurodegenerative disease with no effective treatment, which affects an increasing number of people in Brazil. Immune cells from the adaptive compartment are involved in disease manifestation but whether innate cell functions participate in disease occurrence has not been evaluated. In this study, we analyzed innate cell responses at steady state and after blood cell stimulation using an agonist of the toll-like receptor (TLR)7/8-signaling pathway in blood samples from HTLV-1-infected volunteers, including asymptomatic carriers and HAM/TSP patients. We observed a lower response of IFNα+ DCs and monocytes in HAM/TSP compared to asymptomatic carriers, as a potential consequence of corticosteroid treatments. In contrast, a higher frequency of monocytes producing MIP-1α and pDC producing IL-12 was detected in HAM/TSP blood samples, together with higher IFNγ responsiveness of NK cells, suggesting an increased sensitivity to inflammatory response in HAM/TSP patients compared to asymptomatic carriers. This sustained inflammatory responsiveness could be linked or be at the origin of the neuroinflammatory status in HAM/TSP patients. Therefore, the mechanism underlying this dysregulations could shed light onto the origins of HAM/TSP disease.
Published: 2021
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3. Translation of SARS-CoV-2 gRNA Is Extremely Efficient and Competitive despite a High Degree of Secondary Structures and the Presence of an uORF

Author: Lionel Condé, Omran Allatif, Théophile Ohlmann, and Sylvain de Breyne
Subjects: translation initiation, SARS-CoV-2, eIF4F, mRNA, uORF, Microbiology, QR1-502
Abstract: The SARS-CoV-2 infection generates up to nine different sub-genomic mRNAs (sgRNAs), in addition to the genomic RNA (gRNA). The 5′UTR of each viral mRNA shares the first 75 nucleotides (nt.) at their 5′end, called the leader, but differentiates by a variable sequence (0 to 190 nt. long) that follows the leader. As a result, each viral mRNA has its own specific 5′UTR in term of length, RNA structure, uORF and Kozak context; each one of these characteristics could affect mRNA expression. In this study, we have measured and compared translational efficiency of each of the ten viral transcripts. Our data show that most of them are very efficiently translated in all translational systems tested. Surprisingly, the gRNA 5′UTR, which is the longest and the most structured, was also the most efficient to initiate translation. This property is conserved in the 5′UTR of SARS-CoV-1 but not in MERS-CoV strain, mainly due to the regulation imposed by the uORF. Interestingly, the translation initiation mechanism on the SARS-CoV-2 gRNA 5′UTR requires the cap structure and the components of the eIF4F complex but showed no dependence in the presence of the poly(A) tail in vitro. Our data strongly suggest that translation initiation on SARS-CoV-2 mRNAs occurs via an unusual cap-dependent mechanism.
Published: 2022
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4. Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion

Author: Marie Marotel, Marine Villard, Annabelle Drouillard, Issam Tout, Laurie Besson, Omran Allatif, Marine Pujol, Yamila Rocca, Michelle Ainouze, Guillaume Roblot, Sébastien Viel, Melissa Gomez, Veronique Loustaud, Sophie Alain, David Durantel, Thierry Walzer, Uzma Hasan, and Antoine Marçais
Subjects: natural killer, dysfunction, calcium pathway, mTOR, Medicine, Science, Biology (General), QH301-705.5
Abstract: Antiviral effectors such as natural killer (NK) cells have impaired functions in chronic hepatitis B (CHB) patients. The molecular mechanism responsible for this dysfunction remains poorly characterised. We show that decreased cytokine production capacity of peripheral NK cells from CHB patients was associated with reduced expression of NKp30 and CD16, and defective mTOR pathway activity. Transcriptome analysis of patients NK cells revealed an enrichment for transcripts expressed in exhausted T cells suggesting that NK cell dysfunction and T cell exhaustion employ common mechanisms. In particular, the transcription factor TOX and several of its targets were over-expressed in NK cells of CHB patients. This signature was predicted to be dependent on the calcium-associated transcription factor NFAT. Stimulation of the calcium-dependent pathway recapitulated features of NK cells from CHB patients. Thus, deregulated calcium signalling could be a central event in both T cell exhaustion and NK cell dysfunction occurring during chronic infections.
Published: 2021
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5. Combinatorial Expression of NK Cell Receptors Governs Cell Subset Reactivity and Effector Functions but Not Tumor Specificity

Author: Yamila Rocca, Kevin Pouxvielh, Marie Marotel, Sarah Benezech, Baptiste Jaeger, Omran Allatif, Nathalie Bendriss-Vermare, Antoine Marçais, Thierry Walzer, 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 de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Brain Research Institute [Zurich, Suisse], Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Brain Research Institute, and Universität Zürich [Zürich] = University of Zurich (UZH)
Subjects: Killer Cells, Natural, Mice, Inbred C57BL, Interferon-gamma, Mice, Cell Line, Tumor, Immunology, Animals, Receptors, Natural Killer Cell, Immunology and Allergy, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract: NK cell receptors allow NK cells to recognize targets such as tumor cells. Many of them are expressed on a subset of NK cells, independently of each other, which creates a vast diversity of receptor combinations. Whether these combinations influence NK cell antitumor responses is not well understood. We addressed this question in the C57BL/6 mouse model and analyzed the individual effector response of 444 mouse NK cell subsets, defined by combinations of 12 receptors, against tumor cell lines originating from different tissues and mouse strains. We found a wide range of reactivity among NK subsets, but the same hierarchy of responses was observed for the different tumor types, showing that the repertoire of NK cell receptors does not encode for different tumor specificities but for different intrinsic reactivities. The coexpression of CD27, NKG2A, and DNAM-1 identified subsets with relative cytotoxic specialization, whereas reciprocally, CD11b and KLRG1 defined the best IFN-γ producers. The expression of educating receptors Ly49C, Ly49I, and NKG2A was also strongly correlated with IFN-γ production, but this effect was suppressed by unengaged receptors Ly49A, Ly49F, and Ly49G2. Finally, IL-15 coordinated NK cell effector functions, but education and unbound inhibitory receptors retained some influence on their response. Collectively, these data refine our understanding of the mechanisms governing NK cell reactivity, which could help design new NK cell therapy protocols.
Published: 2022
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6. One-Year Follow-Up of Natural Killer Cell Activity in Multiple Myeloma Patients Treated With Adjuvant Lenalidomide Therapy

Author: Laurie Besson, Emily Charrier, Lionel Karlin, Omran Allatif, Antoine Marçais, Paul Rouzaire, Lucie Belmont, Michel Attal, Christine Lombard, Gilles Salles, Thierry Walzer, and Sébastien Viel
Subjects: natural killer cells, lenalidomide, immunomodulatory drugs, immunomonitoring, innate immunity, multiple myeloma, Immunologic diseases. Allergy, RC581-607
Abstract: Multiple myeloma (MM) is a proliferation of tumoral plasma B cells that is still incurable. Natural killer (NK) cells can recognize and kill MM cells in vitro and can limit MM growth in vivo. Previous reports have shown that NK cell function is impaired during MM progression and suggested that treatment with immunomodulatory drugs (IMIDs) such as lenalidomide (LEN) could enhance it. However, the effects of IMIDs on NK cells have been tested mostly in vitro or in preclinical models and supporting evidence of their effect in vivo in patients is lacking. Here, we monitored NK cell activity in blood samples from 10 MM patients starting after frontline induction chemotherapy (CTX) consisting either of association of bortezomib–lenalidomide–dexamethasone (Velcade Revlimid Dexamethasone) or autologous stem-cell transplantation (SCT). We also monitored NK cell activity longitudinally each month during 1 year, after maintenance therapy with LEN. Following frontline chemotherapy, peripheral NK cells displayed a very immature phenotype and retained poor reactivity toward target cells ex vivo. Upon maintenance treatment with LEN, we observed a progressive normalization of NK cell maturation, likely caused by discontinuation of chemotherapy. However, LEN treatment neither activated NK cells nor improved their capacity to degranulate or to secrete IFN-γ or MIP1-β following stimulation with MHC-I-deficient or antibody-coated target cells. Upon LEN discontinuation, there was no reduction of NK cell effector function either. These results caution against the use of LEN as single therapy to improve NK cell activity in patients with cancer and call for more preclinical assessments of the potential of IMIDs in NK cell activation.
Published: 2018
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7. A third vaccine dose equalizes the levels of effectiveness and immunogenicity of heterologous or homologous COVID-19 vaccine regimens

Author: Nicolas Guibert, Kylian Trepat, Bruno Pozzetto, Laurence Josset, Jean-Baptiste Fassier, Omran Allatif, Kahina Saker, Karen Brengel-Pesce, Thierry Walzer, Philippe Vanhems, and Sophie Trouillet-Assant
Abstract: BackgroungTo cope with the persistence of the Covid-19 epidemic and the decrease in antibody levels following vaccination, a third dose of vaccine has been recommended in the general population. However, several vaccine regimens had been used initially, and the heterologous ChadOx1-S/BNT162b2 regimen had shown better efficacy and immunogenicity than the homologous BNT162b2/BNT162b2 regimen.AimWe wanted to determine if this benefit was retained after the third dose.MethodsWe combined an observational study of SARS-COV-2 infections among vaccinated healthcare workers at the University-Hospital of Lyon, France, with an analysis of immunological parameters before and after the third mRNA vaccine dose.ResultsFollowing the second vaccine dose, heterologous vaccination regimens were more protective against infection than homologous regimens, but this was no longer the case after the third dose. RBD-specific IgG levels and serum neutralization capacity against different SARS-CoV-2 variants were higher after the third dose than after the second dose in the homologous regimen group, but not in the heterologous group.ConclusionThe advantage conferred by heterologous vaccination is lost after the third dose both in terms of protection and immunogenicity. Immunological measurements suggest that heterologous vaccination induces maximal immunity after the second dose, whereas the third dose is required to reach the same level in individuals with a homologous regimen.
Published: 2023
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8. Prior SARS-CoV-2 infection enhances and reshapes spike protein-specific memory induced by vaccination

Author: Véronique Barateau, Loïc Peyrot, Carla Saade, Bruno Pozzetto, Karen Brengel-Pesce, Mad-Hélénie Elsensohn, Omran Allatif, Nicolas Guibert, Christelle Compagnon, Natacha Mariano, Julie Chaix, Sophia Djebali, Jean-Baptiste Fassier, Bruno Lina, Katia Lefsihane, Maxime Espi, Olivier Thaunat, Jacqueline Marvel, Manuel Rosa-Calatrava, Andres Pizzorno, Delphine Maucort-Boulch, Laetitia Henaff, Mitra Saadatian-Elahi, Philippe Vanhems, Stéphane Paul, Thierry Walzer, Sophie Trouillet-Assant, Thierry Defrance, 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 d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Laboratoire Commun de Recherche Hospices Civils de Lyon – bioMérieux (Cancer Biomarkers Research Group), Hospices Civils de Lyon (HCL)-BIOMERIEUX, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche Epidémiologique et de Surveillance Transport Travail Environnement (UMRESTTE UMR_T9405), Université de Lyon-Université de Lyon-Université Gustave Eiffel, BIOASTER Microbiology Technology Institute [Lyon], Service de Biostatistiques [Lyon], and Hôpital Edouard Herriot [CHU - HCL]
Subjects: EPIDEMIOLOGIE, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, SANTE, TOLERANCE HUMAINE, VACCINATION, PANDEMIE, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, General Medicine, SARS-COV-2, MEDICAMENT, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology
Abstract: The diversity of vaccination modalities and infection history are both variables that have an impact on the immune memory of individuals vaccinated against SARS-CoV-2. To gain more accurate knowledge of how these parameters imprint on immune memory, we conducted a long-term follow-up of SARS-CoV-2 spike protein–specific immune memory in unvaccinated and vaccinated COVID-19 convalescent individuals as well as in infection-naïve vaccinated individuals. Here, we report that individuals from the convalescent vaccinated (hybrid immunity) group have the highest concentrations of spike protein–specific antibodies at 6 months after vaccination. As compared with infection-naïve vaccinated individuals, they also display increased frequencies of an atypical mucosa-targeted memory B cell subset. These individuals also exhibited enhanced T H 1 polarization of their SARS-CoV-2 spike protein–specific follicular T helper cell pool. Together, our data suggest that prior SARS-CoV-2 infection increases the titers of SARS-CoV-2 spike protein–specific antibody responses elicited by subsequent vaccination and induces modifications in the composition of the spike protein–specific memory B cell pool that are compatible with enhanced functional protection at mucosal sites.
Published: 2023
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9. Immunogenicity and efficacy of heterologous ChAdOx1–BNT162b2 vaccination

Author: Vincent Legros, Thierry Walzer, Jacqueline Marvel, Jean-Baptiste Fassier, Loïc Peyrot, Sophie Trouillet-Assant, Nicolas Guibert, Véronique Barateau, Thierry Defrance, Bruno Pozzetto, Thibault Andrieu, Bruno Lina, Sophia Djebali, Melyssa Yaugel-Novoa, Solène Denolly, Martine Valette, François-Loïc Cosset, Antonin Bal, Karen Brengel-Pesce, Amélie Massardier-Pilonchery, Omran Allatif, Thomas Bourlet, Bertrand Boson, Marine Villard, Stéphane Paul, 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), Unité Mixte de Recherche Epidémiologique et de Surveillance Transport Travail Environnement (UMRESTTE UMR_T9405), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Gustave Eiffel, Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], ANR-16-CE15-0002,MEMO-SIGN,IMPACT DE LA FORMULATION VACCINALE SUR LA COMPOSITION DES COMPARTMENTS LYMPHOCYTAIRES A MEMOIRE TFH ET B(2016), and ANR-21-COVR-0038,COVIDIgS,Comparaison du role des anticorps IgA/IgM systémique et muqueux dans la physiopathologie et la sévérité de la COVID-19(2021)
Subjects: Adult, Male, MALADIE, COVID19, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Priming (immunology), Heterologous, Hospitals, University, Memory T Cells, Memory B Cells, Immunity, ChAdOx1 nCoV-19, SANTE, Humans, Medicine, BNT162 Vaccine, VIRAL INFECTION, Multidisciplinary, biology, SARS-CoV-2, business.industry, Incidence, Immunogenicity, Vaccination, COVID-19, Middle Aged, Antibodies, Neutralizing, Regimen, Spike Glycoprotein, Coronavirus, Immunology, biology.protein, Female, France, Antibody, business, Immunologic Memory, RNA VACCINES, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Following severe adverse reactions to the AstraZeneca ChAdOx1-S-nCoV-19 vaccine1,2, European health authorities have recommended that patients under the age of 55 who received one dose of ChAdOx1-S-nCoV-19 vaccine receive a second dose of Pfizer BNT162b2 vaccine as a booster. However, the effectiveness and the immunogenicity of this vaccination regimen have not been formally tested. Here, we show that the heterologous ChAdOx1-S-nCoV-19/BNT162b2 combination confers better protection against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection than the homologous BNT162b2/BNT162b2 combination in a real-world observational study of healthcare workers (n=13121). To understand the underlying mechanism, we conducted a longitudinal survey of the anti-spike immunity conferred by each vaccine combination. Both combinations induced strong anti-spike antibody (Ab) responses but sera from heterologous vaccinated individuals displayed a stronger neutralizing activity, regardless of the SARS-CoV-2 variant. This enhanced neutralizing potential was correlated with increased frequencies of switched and activated memory B cells recognizing the SARS-CoV-2 Receptor Binding Domain (RBD). The ChAdOx1-S-nCoV-19 vaccine induced a weaker IgG response but a stronger T cell response than the BNT162b2 vaccine after the priming dose, which could explain the complementarity of both vaccines when used in combination. The heterologous vaccination regimen could therefore be particularly suitable for immune compromised individuals.
Published: 2021
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10. IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection.

Author: Pierre Wallet, Sacha Benaoudia, Amandine Mosnier, Brice Lagrange, Amandine Martin, Helena Lindgren, Igor Golovliov, Fanny Michal, Pauline Basso, Sophia Djebali, Angelina Provost, Omran Allatif, Etienne Meunier, Petr Broz, Masahiro Yamamoto, Bénédicte F Py, Eric Faudry, Anders Sjöstedt, and Thomas Henry
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Guanylate binding proteins (GBPs) are interferon-inducible proteins involved in the cell-intrinsic immunity against numerous intracellular pathogens. The molecular mechanisms underlying the potent antibacterial activity of GBPs are still unclear. GBPs have been functionally linked to the NLRP3, the AIM2 and the caspase-11 inflammasomes. Two opposing models are currently proposed to explain the GBPs-inflammasome link: i) GBPs would target intracellular bacteria or bacteria-containing vacuoles to increase cytosolic PAMPs release ii) GBPs would directly facilitate inflammasome complex assembly. Using Francisella novicida infection, we investigated the functional interactions between GBPs and the inflammasome. GBPs, induced in a type I IFN-dependent manner, are required for the F. novicida-mediated AIM2-inflammasome pathway. Here, we demonstrate that GBPs action is not restricted to the AIM2 inflammasome, but controls in a hierarchical manner the activation of different inflammasomes complexes and apoptotic caspases. IFN-γ induces a quantitative switch in GBPs levels and redirects pyroptotic and apoptotic pathways under the control of GBPs. Furthermore, upon IFN-γ priming, F. novicida-infected macrophages restrict cytosolic bacterial replication in a GBP-dependent and inflammasome-independent manner. Finally, in a mouse model of tularemia, we demonstrate that the inflammasome and the GBPs are two key immune pathways functioning largely independently to control F. novicida infection. Altogether, our results indicate that GBPs are the master effectors of IFN-γ-mediated responses against F. novicida to control antibacterial immune responses in inflammasome-dependent and independent manners.
Published: 2017
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11. High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors

Author: Antoine Marçais, Marie Marotel, Sophie Degouve, Alice Koenig, Sébastien Fauteux-Daniel, Annabelle Drouillard, Heinrich Schlums, Sébastien Viel, Laurie Besson, Omran Allatif, Mathieu Bléry, Eric Vivier, Yenan Bryceson, Olivier Thaunat, and Thierry Walzer
Subjects: natural killer, cell signaling, mTOR, education, activation threshold, Medicine, Science, Biology (General), QH301-705.5
Abstract: NK cell education is the process through which chronic engagement of inhibitory NK cell receptors by self MHC-I molecules preserves cellular responsiveness. The molecular mechanisms responsible for NK cell education remain unclear. Here, we show that mouse NK cell education is associated with a higher basal activity of the mTOR/Akt pathway, commensurate to the number of educating receptors. This higher activity was dependent on the SHP-1 phosphatase and essential for the improved responsiveness of reactive NK cells. Upon stimulation, the mTOR/Akt pathway amplified signaling through activating NK cell receptors by enhancing calcium flux and LFA-1 integrin activation. Pharmacological inhibition of mTOR resulted in a proportional decrease in NK cell reactivity. Reciprocally, acute cytokine stimulation restored reactivity of hyporesponsive NK cells through mTOR activation. These results demonstrate that mTOR acts as a molecular rheostat of NK cell reactivity controlled by educating receptors and uncover how cytokine stimulation overcomes NK cell education.
Published: 2017
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12. Assessing mycoplasma contamination of cell cultures by qPCR using a set of universal primer pairs targeting a 1.5 kb fragment of 16S rRNA genes.

Author: Audrey Jean, Florence Tardy, Omran Allatif, Isabelle Grosjean, Bariza Blanquier, and Denis Gerlier
Subjects: Medicine, Science
Abstract: Mycoplasmas (a generic name for Mollicutes) are a predominant bacterial contaminant of cell culture and cell derived products including viruses. This prokaryote class is characterized by very small size and lack of a cell wall. Consequently, mycoplasmas escape ultrafiltration and visualization under routine microscopic examination, hence the ease with which cells in culture can be contaminated, with routinely more than 10% of cell lines being contaminated. Mycoplasma are a formidable threat both in fundamental research by perverting a whole range of cell properties and functions and in the pharmacological use of cells and cell derived products. Although many methods have been developed, there is still a need for a sensitive, universal assay. Here is reported the development and validation of a quantitative polymerase chain reaction (qPCR) based on the amplification of a 1.5 kb fragment covering the 16S rDNA of the Mollicute class by real-time PCR using universal U1 and U8 degenerate primers. The method includes the addition of a DNA loading probe to each sample to monitor DNA extraction and the absence of PCR inhibitors in the extracted DNA, a positive mycoplasma 16S rDNA traceable reference sample to exclude any accidental contamination of an unknown sample with this reference DNA, an analysis procedure based on the examination of the melting curve and the size of the PCR amplicon, followed by quantification of the number of 16S rDNA copies (with a lower limit of 19 copies) when relevant, and, if useful, the identification of the contaminating prokaryote by sequencing. The method was validated on a collection of mycoplasma strains and by testing over 100 samples of unknown contamination status including stocks of viruses requiring biosafety level 2, 3 or 4 containments. When compared to four established methods, the m16S_qPCR technique exhibits the highest sensitivity in detecting mycoplasma contamination.
Published: 2017
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13. Immunoprofiling of fresh HAM/TSP blood samples shows altered innate cell responsiveness

Author: Omran Allatif, Noemia Mie Orii, Hélène Dutartre, Nicolas Futsch, Augusto César Penalva de Oliveira, Jorge Casseb, Brenda Rocamonde, and Renaud Mahieux
Subjects: Male, RNA viruses, Physiology, Cell, RC955-962, Stimulation, NK cells, Pathology and Laboratory Medicine, Monocytes, Cohort Studies, Blood cell, White Blood Cells, Medical Conditions, Animal Cells, immune system diseases, Immune Physiology, hemic and lymphatic diseases, Arctic medicine. Tropical medicine, Tropical spastic paraparesis, Medicine and Health Sciences, Receptor, Immune Response, Human T-lymphotropic virus 1, Innate Immune System, T Cells, virus diseases, Middle Aged, Interleukin-12, Paraparesis, Tropical Spastic, Killer Cells, Natural, Leukemia, Infectious Diseases, medicine.anatomical_structure, Medical Microbiology, Viral Pathogens, Viruses, Cytokines, Female, Cellular Types, Pathogens, Public aspects of medicine, RA1-1270, Brazil, Research Article, Adult, endocrine system, Immune Cells, Inflammatory Diseases, Immunology, Antigen-Presenting Cells, Microbiology, Immune system, Retroviruses, medicine, Humans, Microbial Pathogens, Blood Cells, business.industry, Organisms, Public Health, Environmental and Occupational Health, Biology and Life Sciences, Dendritic Cells, Cell Biology, Htlv-1, Molecular Development, medicine.disease, Immunity, Innate, Immune System, business, Asymptomatic carrier, Developmental Biology
Abstract: The Human T-cell Leukemia Virus-1 (HTLV-1)-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a devastating neurodegenerative disease with no effective treatment, which affects an increasing number of people in Brazil. Immune cells from the adaptive compartment are involved in disease manifestation but whether innate cell functions participate in disease occurrence has not been evaluated. In this study, we analyzed innate cell responses at steady state and after blood cell stimulation using an agonist of the toll-like receptor (TLR)7/8-signaling pathway in blood samples from HTLV-1-infected volunteers, including asymptomatic carriers and HAM/TSP patients. We observed a lower response of IFNα+ DCs and monocytes in HAM/TSP compared to asymptomatic carriers, as a potential consequence of corticosteroid treatments. In contrast, a higher frequency of monocytes producing MIP-1α and pDC producing IL-12 was detected in HAM/TSP blood samples, together with higher IFNγ responsiveness of NK cells, suggesting an increased sensitivity to inflammatory response in HAM/TSP patients compared to asymptomatic carriers. This sustained inflammatory responsiveness could be linked or be at the origin of the neuroinflammatory status in HAM/TSP patients. Therefore, the mechanism underlying this dysregulations could shed light onto the origins of HAM/TSP disease., Author summary The infection by the Human T-cell Leukemia Virus-1 (HTLV-1) is quite frequent in Brazil. Between 1–5% of infected individuals develop a devastating neurodegenerative disease (HAM/TSP) as a result of a sustained inflammation in the central nervous system, with no effective treatment. So far, inflammation has been linked to the deregulated activation of T-cells, but the role of innate cells has not been investigated yet. In this work, we aimed to characterize the responsiveness of innate cells, as this immune population is cornerstone of efficient immune response, but also might participate in disease exacerbation found in chronic infection. Our findings suggest an impaired antiviral response and increased inflammatory responsiveness by dendritic cells and monocytes in HAM/TSP patients compared to asymptomatic carriers. This sustained inflammatory responsiveness upon innate cell activation could participate in the establishment of the HAM/TSP disease.
Published: 2021

14. A Dietary Supplement Containing Cinnamon, Chromium and Carnosine Decreases Fasting Plasma Glucose and Increases Lean Mass in Overweight or Obese Pre-Diabetic Subjects: A Randomized, Placebo-Controlled Trial.

Author: Yuejun Liu, Aurélie Cotillard, Camille Vatier, Jean-Philippe Bastard, Soraya Fellahi, Marie Stévant, Omran Allatif, Clotilde Langlois, Séverine Bieuvelet, Amandine Brochot, Angèle Guilbot, Karine Clément, and Salwa W Rizkalla
Subjects: Medicine, Science
Abstract: Preventing or slowing the progression of prediabetes to diabetes is a major therapeutic issue.Our aim was to evaluate the effects of 4-month treatment with a dietary supplement containing cinnamon, chromium and carnosine in moderately obese or overweight pre-diabetic subjects, the primary outcome being change in fasting plasma glucose (FPG) level. Other parameters of plasma glucose homeostasis, lipid profile, adiposity and inflammatory markers were also assessed.In a randomized, double-blind, placebo-controlled study, 62 subjects with a FPG level ranging from 5.55 to 7 mmol/L and a body mass index ≥ 25 kg/m(2), unwilling to change their dietary and physical activity habits, were allocated to receive a 4-month treatment with either 1.2 g/day of the dietary supplement or placebo. Patients were followed up until 6 months post-randomization.Four-month treatment with the dietary supplement decreased FPG compared to placebo (-0.24 ± 0.50 vs +0.12 ± 0.59 mmol/L, respectively, p = 0.02), without detectable significant changes in HbA1c. Insulin sensitivity markers, plasma insulin, plasma lipids and inflammatory markers did not differ between the treatment groups. Although there were no significant differences in changes in body weight and energy or macronutrient intakes between the two groups, fat-free mass (%) increased with the dietary supplement compared to placebo (p = 0.02). Subjects with a higher FPG level and a milder inflammatory state at baseline benefited most from the dietary supplement.Four-month treatment with a dietary supplement containing cinnamon, chromium and carnosine decreased FPG and increased fat-free mass in overweight or obese pre-diabetic subjects. These beneficial effects might open up new avenues in the prevention of diabetes.ClinicalTrials.gov NCT01530685.
Published: 2015
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15. Correction: A Dietary Supplement Containing Cinnamon, Chromium and Carnosine Decreases Fasting Plasma Glucose and Increases Lean Mass in Overweight or Obese Pre-Diabetic Subjects: A Randomized, Placebo-Controlled Trial.

Author: Yuejun Liu, Aurélie Cotillard, Camille Vatier, Jean-Philippe Bastard, Soraya Fellahi, Marie Stévant, Omran Allatif, Clotilde Langlois, Séverine Bieuvelet, Amandine Brochot, Angèle Guilbot, Karine Clément, and Salwa W Rizkalla
Subjects: Medicine, Science
Published: 2015
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16. Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2-infected cells

Author: Remi Pescamona, Elodie Decembre, Thierry Walzer, Manon Venet, Alicia Bellomo, Alexandre Belot, Emiliano P. Ricci, Marine Villard, Magali Perret, Sophie Trouillet-Assant, Garima Joshi, Helena Paidassi, Omran Allatif, David Cluet, Margarida Sa Ribeiro, and Marlène Dreux
Subjects: Coronavirus disease 2019 (COVID-19), Viral replication, Effector, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, hemic and immune systems, In patient, Viral rna, macromolecular substances, Viral spread, Biology, Cell adhesion
Abstract: Type I and III interferons (IFN-I/λ) are key antiviral mediators against SARS-CoV-2 infection. Here, we demonstrate that plasmacytoid dendritic cells (pDCs) are the predominant IFN-I/λ source following their sensing of SARS-CoV-2-infected cells. Mechanistically, this short-range sensing by pDCs requires sustained integrin-mediated cell adhesion with infected cells. In turn, pDCs restrict viral spread by an IFN-I/λ response directed toward SARS-CoV-2-infected cells. This specialized function enables pDCs to efficiently turn-off viral replication, likelyviaa local response at the contact site with infected cells. By exploring the pDC response in SARS-CoV-2 patients, we further demonstrate that pDC responsiveness inversely correlates with the severity of the disease. The pDC response is particularly impaired in severe COVID-19 patients. Overall, we propose that pDC activation is essential to control SARS-CoV-2-infection. Failure to unfold this response could be key to understand severe cases of COVID-19.
Published: 2021
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17. Polyclonal expansion of TCR Vb 21.3 + CD4 + and CD8 + T cells is a hallmark of multisystem inflammatory syndrome in children

Author: Olivier Dauwalder, David Klatzmann, Marie Duperril, Marion Moreews, Christine Lombard, Behrouz Kassai, Fanny Bajolle, Jean-Laurent Casanova, Anne-Laure Mathieu, Guillaume Monneret, Magali Perret, Rémi Pescarmona, Aurélie Portefaix, Jacqueline Marvel, Laurent Abel, Christophe Malcus, Tiphaine Louazon, Anne Moulin-Zinsch, Mehdi Mezidi, Lisa Giovannini-Chami, Omran Allatif, Hugues Patural, Thierry Walzer, Emilie Chopin, Francois Vandenesh, Encarnita Mariotti-Ferrandiz, Fabienne Venet, Céline Dupieux, Valérie Launay, Paul Bastard, Sophie Trouillet-Assant, Jean-Christophe Richard, Olivier Thaunat, Shen-Ying Zhang, Marine Villard, Samira Khaldi-Plassart, Kahina Saker, Alexandre Belot, Sophia Djebali, Marlène Dreux, Alicia Bellomo, Isabelle Rouvet, Robin Pouyau, Etienne Javouhey, Margaux Guerder, Sonia Teyssedre, Valérie Dubois, Kenz Le Gouge, Hugues Flodrops, Jean-Marie De Guillebon, 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), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l’enfant / National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children [Lyon] (RAISE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hôpital Edouard Herriot [CHU - HCL], Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre National de Reference des Staphylocoques, Université de Lyon, Centre hospitalier de Valence, Hôpital Louis Pradel [CHU - HCL], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), CIC CHU Lyon (inserm), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Rockefeller University [New York], Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Hôpital de la Croix-Rousse [CHU - HCL], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), 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)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [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)-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)-Sorbonne Université (SU), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-16-RHUS-0001,iMAP,iMAP(2016), Référent HAL, CIRI, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, T cell, [SDV]Life Sciences [q-bio], Immunology, T-cell receptor, Toxic shock syndrome, General Medicine, Human leukocyte antigen, Biology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Antigen, medicine, Cytotoxic T cell, 030212 general & internal medicine, Cytokine storm, CD8
Abstract: International audience; Multisystem inflammatory syndrome in children (MIS-C) is a delayed and severe complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease (KD) and toxic shock syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared with 16 KD, 58 TSS, and 42 coronavirus disease 2019 (COVID-19) cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFN-γ, sCD25, MCP1, and IL-1RA) in MIS-C, TSS, and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of patients with MIS-C and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3 + T cells from patients with MIS-C expressed high levels of HLA-DR, CD38, and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS, and acute COVID-19.
Published: 2021
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18. Immunoprofiling of HTLV-1-infected individuals shows altered innate cell responsiveness in HAM/TSP patients

Author: Caseb J, Hélène Dutartre, Nicolas Futsch, Renaud Mahieux, Penalva de Oliveira Ac, Brenda Rocamonde, Omran Allatif, and Orii N
Subjects: Innate immune system, Cell, virus diseases, Biology, medicine.disease, Blood cell, Myelopathy, Leukemia, medicine.anatomical_structure, immune system diseases, Immunology, Tropical spastic paraparesis, medicine, Receptor, Asymptomatic carrier
Abstract: The Human T-cell Leukemia Virus-1 (HTLV-1)-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a devastating neurodegenerative disease with no effective treatment, which affects an increasing number of people in Brazil. A biological blood factor allowing the prediction of the disease occurrence is so far not available. In this study, we analyzed innate immunity responses at steady state and after blood cell stimulation using an agonist of the toll-like receptor (TLR)7/8-signaling pathway in blood samples from HTLV-1-infected volunteers, including asymptomatic carriers and HAM/TSP patients. We observed a lower responsiveness in dendritic cells to produce IFNα. Moreover, we found higher production of IL-12 and Mip-1α by monocytes together with higher levels of IFNγ produced by Natural Killer cells. These deregulations could represent a signature for progression towards HAM/TSP.
Published: 2021
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19. Polyclonal expansion of TCR Vbeta 21.3

Author: Marion, Moreews, Kenz, Le Gouge, Samira, Khaldi-Plassart, Rémi, Pescarmona, Anne-Laure, Mathieu, Christophe, Malcus, Sophia, Djebali, Alicia, Bellomo, Olivier, Dauwalder, Magali, Perret, Marine, Villard, Emilie, Chopin, Isabelle, Rouvet, Francois, Vandenesh, Céline, Dupieux, Robin, Pouyau, Sonia, Teyssedre, Margaux, Guerder, Tiphaine, Louazon, Anne, Moulin-Zinsch, Marie, Duperril, Hugues, Patural, Lisa, Giovannini-Chami, Aurélie, Portefaix, Behrouz, Kassai, Fabienne, Venet, Guillaume, Monneret, Christine, Lombard, Hugues, Flodrops, Jean-Marie, De Guillebon, Fanny, Bajolle, Valérie, Launay, Paul, Bastard, Shen-Ying, Zhang, Valérie, Dubois, Olivier, Thaunat, Jean-Christophe, Richard, Mehdi, Mezidi, Omran, Allatif, Kahina, Saker, Marlène, Dreux, Laurent, Abel, Jean-Laurent, Casanova, Jacqueline, Marvel, Sophie, Trouillet-Assant, David, Klatzmann, Thierry, Walzer, Encarnita, Mariotti-Ferrandiz, Etienne, Javouhey, and Alexandre, Belot
Subjects: Adult, CD4-Positive T-Lymphocytes, SARS-CoV-2, Child, Preschool, Receptors, Antigen, T-Cell, alpha-beta, COVID-19, Cytokines, Humans, HLA-DR Antigens, CD8-Positive T-Lymphocytes, Child, Lymphocyte Activation, Systemic Inflammatory Response Syndrome
Abstract: Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro
Published: 2021

20. Author response: Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion

Author: Issam Tout, Melissa Gomez, Thierry Walzer, Sébastien Viel, Yamila Rocca, David Durantel, Sophie Alain, Marine Villard, Marine Pujol, Michelle Ainouze, Antoine Marçais, Veronique Loustaud, Omran Allatif, Marie Marotel, Laurie Besson, Guillaume Roblot, Uzma Hasan, and Annabelle Drouillard
Subjects: medicine.anatomical_structure, Chronic hepatitis, business.industry, T cell, Immunology, Medicine, business, Peripheral
Published: 2021
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21. Combinatorial Expression of NK Cell Receptors Governs Cell Subset Reactivity and Effector Functions But Not Tumor Specificity

Author: Kevin Pouxvielh, Marie Marotel, Thierry Walzer, Omran Allatif, Baptiste N. Jaeger, Antoine Marçais, Yamila Rocca, and Nathalie Bendriss-Vermare
Subjects: Cell therapy, medicine.anatomical_structure, Integrin alpha M, biology, Effector, Repertoire, T cell subset, Cell, medicine, biology.protein, Cytotoxic T cell, Receptor, Cell biology
Abstract: Natural Killer (NK) cell receptors allow NK cells to recognize targets such as tumor cells. Many of them are expressed on a subset of NK cells, independently of each other, which creates a vast diversity of receptor combinations. Whether these combinations influence NK cell anti-tumor responses is not well understood. We addressed this question in the C57BL/6 mouse model and analyzed the individual effector response of 444 mouse NK cell subsets, defined by combinations of 12 receptors, against tumor cell lines of different tissue origins. We found a wide range of reactivity among NK subsets, but the same hierarchy of responses was observed for the different tumor types, showing that the repertoire of NK cell receptors does not encode for different tumor specificities but for different intrinsic reactivities. The co-expression of CD27, NKG2A, and DNAM-1 identified subsets with relative cytotoxic specialization, while reciprocally CD11b and KLRG1 defined best IFNg producers. The expression of educating receptors Ly49C, Ly49I, and NKG2A was also strongly correlated with IFNg production but this effect was suppressed by unengaged receptors Ly49A, Ly49F, and Ly49G2. Finally, IL-15 coordinated NK cell effector functions but education and unbound inhibitory receptors retained some influence on their response. Collectively, these data refine our understanding of the mechanisms governing NK cell reactivity, which could help design new NK cell therapy protocols.
Published: 2021
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22. DGINN, an automated and highly-flexible pipeline for the detection of genetic innovations on protein-coding genes

Author: Andrea Cimarelli, Laurent Guéguen, Lucie Etienne, Quentin Ganivet, Lea Picard, Omran Allatif, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), BioInformatique et BioStatistiques (BIBS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Interaction hôte pathogène lors de l'infection lentivirale – Host-Pathogen Interaction during Lentiviral Infection (LP2L), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), 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), 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)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
Subjects: Protein coding, 0303 health sciences, Computer science, [SDV]Life Sciences [q-bio], Computational biology, Pipeline (software), Ranking (information retrieval), 03 medical and health sciences, 0302 clinical medicine, Gene duplication, Identification (biology), Adaptation, Gene, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Adaptive evolution
Abstract: Adaptive evolution has shaped major biological processes. Finding the protein-coding genes and the sites that have been subjected to adaptation during evolutionary time is a major endeavor. However, very few methods fully automate the identification of positively selected genes, and widespread sources of genetic innovations as gene duplication and recombination are absent from most pipelines. Here, we developed DGINN, a highly-flexible and public pipeline to Detect Genetic INNovations and adaptive evolution in protein-coding genes. DGINN automates, from a gene’s sequence, all steps of the evolutionary analyses necessary to detect the aforementioned innovations, including the search for homologues in databases, assignation of orthology groups, identification of duplication and recombination events, as well as detection of positive selection using five different methods to increase precision and ranking of genes when a large panel is analyzed. DGINN was validated on nineteen genes with previously-characterized evolutionary histories in primates, including some engaged in host-pathogen arms-races. The results obtained with DGINN confirm and also expand results from the literature, establishing DGINN as an efficient tool to automatically detect genetic innovations and adaptive evolution in diverse datasets, from the user’s gene of interest to a large gene list in any species range.
Published: 2020
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23. DGINN, an automated and highly-flexible pipeline for the detection of genetic innovations on protein-coding genes

Author: Lea, Picard, Quentin, Ganivet, Omran, Allatif, Andrea, Cimarelli, Laurent, Guéguen, and Lucie, Etienne
Subjects: Evolution, Molecular, Primates, Narese/24, AcademicSubjects/SCI00010, Databases, Genetic, Animals, Genetic Variation, Proteins, Methods Online, Selection, Genetic, Narese/7
Abstract: Adaptive evolution has shaped major biological processes. Finding the protein-coding genes and the sites that have been subjected to adaptation during evolutionary time is a major endeavor. However, very few methods fully automate the identification of positively selected genes, and widespread sources of genetic innovations such as gene duplication and recombination are absent from most pipelines. Here, we developed DGINN, a highly-flexible and public pipeline to Detect Genetic INNovations and adaptive evolution in protein-coding genes. DGINN automates, from a gene's sequence, all steps of the evolutionary analyses necessary to detect the aforementioned innovations, including the search for homologs in databases, assignation of orthology groups, identification of duplication and recombination events, as well as detection of positive selection using five methods to increase precision and ranking of genes when a large panel is analyzed. DGINN was validated on nineteen genes with previously-characterized evolutionary histories in primates, including some engaged in host-pathogen arms-races. Our results confirm and also expand results from the literature, including novel findings on the Guanylate-binding protein family, GBPs. This establishes DGINN as an efficient tool to automatically detect genetic innovations and adaptive evolution in diverse datasets, from the user's gene of interest to a large gene list in any species range.
Published: 2020

24. A longitudinal study of SARS-CoV-2 infected patients shows high correlation between neutralizing antibodies and COVID-19 severity

Author: Guillaume Thierry, Philippe Berthelot, Solène Denolly, Thomas Bourlet, Josselin Rigaill, François-Loïc Cosset, Sylvie Pillet, Manon Vogrig, Carole Pélissier, Elisabeth Botelho-Nevers, Thierry Walzer, Bruno Pozzetto, Bertrand Boson, Omran Allatif, Vincent Legros, Stéphane Paul, Paul O. Verhoeven, Florence Grattard, and Sylvie Gonzalo
Subjects: biology, business.industry, viruses, virus diseases, Disease, Asymptomatic, Pathogenesis, Titer, Immune system, Intensive care, Immunology, biology.protein, Medicine, Antibody, medicine.symptom, business, Neutralizing antibody
Abstract: Understanding the immune responses elicited by SARS-CoV-2 infection is critical in terms of protection from re-infection and, thus, for public health policy and for vaccine development against the COVID-19. Here, using either live SARS-CoV-2 particles or retroviruses pseudotyped with the SARS-CoV-2 S viral surface protein (Spike), we studied the neutralizing antibody (nAb) response in serum specimens from a cohort of 140 SARS-CoV-2 qPCR-confirmed patients, including patient with mild symptoms but also more severe form including those that require intensive care. We show that nAb titers were strongly correlated with disease severity and with anti-Spike IgG levels. Indeed, patients from intensive care units exhibited high nAb titers, whereas patients with milder disease symptoms displayed heterogenous nAb titers and asymptomatic or exclusive outpatient care patients had no or poor nAb levels. We found that the nAb activity in SARS-CoV-2-infected patients displayed a relatively rapid decline after recovery, as compared to individuals infected with alternative coronaviruses. We show the absence of cross-neutralization between endemic coronaviruses and SARS-CoV-2, indicating that previous infection by human coronaviruses may not generate protective nAb against SARS-CoV-2 infection. Finally, we found that the D614G mutation in the Spike protein, which has recently been identified as the major variant now found in Europe, does not allow neutralization escape. Altogether, our results contribute to the understanding of the immune correlate of SARS-CoV-2 induced disease and claim for a rapid evaluation of the role of the humoral response in the pathogenesis of SARS-CoV-2.
Published: 2020
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25. Massive clonal expansion of polycytotoxic skin and blood CD8

Author: Axel Patrice, Villani, Aurore, Rozieres, Benoît, Bensaid, Klara Kristin, Eriksson, Amandine, Mosnier, Floriane, Albert, Virginie, Mutez, Océane, Brassard, Tugba, Baysal, Mathilde, Tardieu, Omran, Allatif, Floriane, Fusil, Thibault, Andrieu, Denis, Jullien, Valérie, Dubois, Catherine, Giannoli, Henri, Gruffat, Marc, Pallardy, François-Loïc, Cosset, Audrey, Nosbaum, Osami, Kanagawa, Janet L, Maryanski, Daniel, Yerly, Jean-François, Nicolas, and Marc, Vocanson
Subjects: integumentary system, musculoskeletal, neural, and ocular physiology, Immunology, Receptors, Antigen, T-Cell, SciAdv r-articles, macromolecular substances, CD8-Positive T-Lymphocytes, Clone Cells, Immunophenotyping, nervous system, Stevens-Johnson Syndrome, Humans, Prospective Studies, Research Articles, Research Article
Abstract: This study highlights the key role of polycytotoxic CD8+ T cells in the severity of toxic epidermal necrolysis., Toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction. To better understand why skin symptoms are so severe, we conducted a prospective immunophenotyping study on skin and blood. Mass cytometry results confirmed that effector memory polycytotoxic CD8+ T cells (CTLs) are the main leucocytes in TEN blisters at the acute phase. Deep T cell receptor (TCR) repertoire sequencing identified massive expansion of unique CDR3 clonotypes in blister cells. The same clones were highly expanded in patient’s blood, and the degree of their expansion showed significant correlation with disease severity. By transducing α and β chains of the expanded clonotypes into a TCR-defective cell line, we confirmed that those cells were drug specific. Collectively, these results suggest that the relative clonal expansion and phenotype of skin-recruited CTLs condition the clinical presentation of cutaneous adverse drug reactions.
Published: 2020

26. Peripheral Natural Killer cells from chronic hepatitis B patients display molecular hallmarks of T cell exhaustion

Author: Melissa Gomez, Issam Tout, Yamila Rocca, Uzma Hasan, Marine Pujol, Guillaume Roblot, David Durantel, Marine Villard, Michelle Ainouze, Sophie Alain, Veronique Loustaud, Antoine Marçais, Omran Allatif, Marie Marotel, Sébastien Viel, Laurie Besson, and Thierry Walzer
Subjects: Transcriptome, Thymocyte, Immune system, medicine.anatomical_structure, T cell, Cell, Immunology, medicine, NFAT, CD16, Biology, PI3K/AKT/mTOR pathway
Abstract: A significant proportion of individuals infected by HBV develops chronic infection. Antiviral effectors such as Natural Killer (NK) cells have impaired functions in these patients, but the molecular mechanism responsible for this dysfunction remains poorly characterized. Here, we show that peripheral NK cells from chronic hepatitis B (CHB) patients have a defective capacity to produce IFN-γ, MIP1-β and TNF-α but retain an intact killing capacity. This functional phenotype was associated with a decrease in the expression of NKp30 and CD16, combined with defects in IL-15 stimulation of the mTOR pathway. Transcriptome analysis of NK cells in CHB patients further revealed a strong enrichment for transcripts typically expressed in exhausted T cells suggesting that NK cell dysfunction and T cell exhaustion rely on common molecular mechanisms. In particular, the transcription factor thymocyte selection-associated HMG box protein (TOX) and several of its targets, including immune checkpoints, were over-expressed in NK cells of CHB patients. This T cell exhaustion signature was predicted to be dependent on the calcium (Ca2+)-associated transcription factor NFAT. In line with this, when stimulating the Ca2+-dependent pathway in isolation, we recapitulated the dysfunctional phenotype. Thus, deregulated Ca2+ signalling could be a central event in both T cell exhaustion and NK cell dysfunction that occur during chronic infections.
Published: 2020
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27. Analyse moléculaire des patch-tests douteux aux médicaments

Author: Audrey Nosbaum, F. Hacard, Omran Allatif, Amandine Mosnier, L. Crumbach, J.-F. Nicolas, Marine-Alexia Lefevre, Marc Vocanson, and Frédéric Bérard
Subjects: Immunology and Allergy
Abstract: Introduction Le patch test (PT) est un outil cle pour l’exploration des reactions d’hypersensibilite retardees cutanees (HRC) medicamenteuses. La lecture des PT aux medicaments suit les memes criteres que ceux utilises pour les PT testes avec d’autres produits chimiques, couramment utilises dans l’exploration des eczemas de contact. Les PT douteux ne sont generalement pas consideres comme cliniquement pertinents, mais il n’y a pas de recommandations specifiques concernant leur prise en charge pour les HRC aux medicaments. L’objectif est d’etudier le profil moleculaire cutane des PT douteux aux medicaments dans les HRC fortement evocatrices d’allergie, et le comparer a celui retrouve dans les PT negatifs et positifs. Methodes A partir de biopsies de PT, nous avons etudie retrospectivement par RT-qPCR l’expression genique de six biomarqueurs specifiques impliques dans les reactions d’HRC medicamenteuse (CD4, CD8a, granzyme B, granulysine, IFNg et CD69). Les resultats sont exprimes en ratio par rapport a une peau saine controle. Resultats Onze HRC aux medicaments ont ete explorees et quinze PT biopsies (quatre PT negatifs, quatre PT douteux, et sept PT positifs). Une augmentation significative de l’expression de CD8a, granzyme B, granulysin et CD69 a ete retrouvee dans les PT positifs et douteux par rapport aux PT negatifs. Il n’a pas ete retrouve de differences significatives concernant l’expression de tous les biomarqueurs entre le groupe des PT douteux et celui des PT positifs. Conclusion Lorsque l’histoire clinique est tres evocatrice d’une reaction d’hypersensibilite retardee allergique, les PT douteux pourraient etre consideres comme pertinents, et donc comme positifs. L’etude moleculaire par RT-qPCR pourrait conduire a redefinir la classification des PT dans l’etude des HRC aux medicaments, et ainsi securiser leur prise en charge.
Published: 2021
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28. Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome

Author: Véronique Hentgen, Flora Magnotti, Agnès Duquesne, Thomas Henry, Bénédicte F. Py, Marine Desjonquères, Mathilde Penel-Page, Yvan Jamilloux, Mathieu Gerfaud-Valentin, Pascal Sève, Alexandre Belot, Luca Cantarini, Vanessa Remy-Piccolo, Amandine Martin, Rolando Cimaz, Thierry Walzer, Lucie Lefeuvre, Audrey Laurent, Emilie Bourdonnay, Omran Allatif, Sarah Benezech, Inflammasome, Infections bactériennes et autoinflammation, Inflammasome, Bacterial Infections and Autoinflammation (I2BA), 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)-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), Service de Médecine Interne [Hôpital Croix Rousse, CHU Lyon], CHU Lyon-Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL), AOU Meyer, Interdepartmental Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Policlinico Le Scotte, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, BioInformatique et BioStatistiques (BIBS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Centre de Référence des Maladies AutoInflammatoires (CeRéMAI), Centre Hospitalier de Versailles André Mignot (CHV), L'Hôpital Nord-Ouest [Villefranche sur Saône], Inflammasome NLRP3 – NLRP3 Inflammasome, 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)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)
Subjects: Male, Salmonella typhimurium, rho GTP-Binding Proteins, 0301 basic medicine, Inflammasomes, Autoinflammation, Familial mediterranean fever, IL-18, IL-1β, Inflammasome, MEFV, NLRC4, NLRP3, Pyrin, Adenosine Triphosphate, Adolescent, Adult, Antigens, Bacterial, Bacterial Proteins, Bacterial Toxins, CARD Signaling Adaptor Proteins, Calcium-Binding Proteins, Case-Control Studies, Cell Death, Child, Child, Preschool, Familial Mediterranean Fever, Female, Healthy Volunteers, Humans, Interleukin-18, Interleukin-1beta, Ionophores, Middle Aged, Monocytes, Mutation, NLR Family, Pyrin Domain-Containing 3 Protein, Nigericin, Rheumatology, Pharmacology (medical), Familial Mediterranean fever, Pyrin domain, Exon, 0302 clinical medicine, ComputingMilieux_MISCELLANEOUS, Bacterial, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interleukin 18, medicine.drug, Clostridium difficile toxin B, NLR Family, 03 medical and health sciences, medicine, Antigens, Preschool, 030203 arthritis & rheumatology, business.industry, medicine.disease, Pyrin Domain-Containing 3 Protein, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 030104 developmental biology, Immunology, business
Abstract: Objectives FMF is the most frequent autoinflammatory disease and is associated in most patients with bi-allelic MEFV mutations. MEFV encodes Pyrin, an inflammasome sensor activated following RhoGTPase inhibition. The functional consequences of MEFV mutations on the ability of Pyrin variants to act as inflammasome sensors are largely unknown. The aim of this study was to assess whether MEFV mutations affect the ability of Pyrin to detect RhoGTPase inhibition and other inflammasome stimuli. Methods IL-1β and IL-18 released by monocytes from healthy donors (HDs) and FMF patients were measured upon specific engagement of the Pyrin, NLRP3 and NLRC4 inflammasomes. Cell death kinetics following Pyrin activation was monitored in real time. Results Monocytes from FMF patients secreted significantly more IL-1β and IL-18 and died significantly faster than HD monocytes in response to low concentrations of Clostridium difficile toxin B (TcdB), a Pyrin-activating stimulus. Monocytes from patients bearing two MEFV exon 10 pathogenic variants displayed an increased Pyrin inflammasome response compared with monocytes from patients with a single exon 10 pathogenic variant indicating a gene-dosage effect. Using a short priming step, the response of monocytes from FMF patients to NLRP3- and NLRC4-activating stimuli was normal indicating that MEFV mutations trigger a specific hypersensitivity of monocytes to low doses of a Pyrin-engaging stimulus. Conclusion Contrary to the NLRP3 mutations described in cryopyrin-associated periodic syndrome, FMF-associated MEFV mutations do not lead to a constitutive activation of Pyrin. Rather, FMF-associated mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome without affecting other canonical inflammasomes.
Published: 2017
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29. A genome‐wide screen identifies IRF2 as a key regulator of caspase‐4 in human cells

Author: Sacha Benaoudia, Amandine Martin, Marta Puig Gamez, Gabrielle Gay, Brice Lagrange, Maxence Cornut, Kyrylo Krasnykov, Jean‐Baptiste Claude, Cyril F Bourgeois, Sandrine Hughes, Benjamin Gillet, Omran Allatif, Antoine Corbin, Romeo Ricci, Thomas Henry, Inflammasome, Infections bactériennes et autoinflammation, Inflammasome, Bacterial Infections and Autoinflammation (I2BA), 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)-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), 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), National Infrastructure INGESTEM, Université Paris Sud, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), BioInformatique et BioStatistiques (BIBS), ANR-16-CE15-0011,MANKIND,Interactions entre les macrophages et les cellules Natural Killer dans les infections par les bactéries intracellulaires(2016), Inflammasome, Bacterial Infections and Autoinflammation, 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), BioInformatique et BioStatistiques (2-BIBS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon)
Subjects: Lipopolysaccharides, [SDV]Life Sciences [q-bio], Caspase 4, Caspase-11, Biochemistry, Monocytes, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Clustered Regularly Interspaced Short Palindromic Repeats, News & Views, Molecular Biology, Transcription factor, 030304 developmental biology, 0303 health sciences, Cell Death, biology, Effector, Intracellular Signaling Peptides and Proteins, Pyroptosis, Inflammasome, U937 Cells, Phosphate-Binding Proteins, Caspases, Initiator, Cell biology, IRF1, biology.protein, Interferon Regulatory Factor-2, 030217 neurology & neurosurgery, Interferon Regulatory Factor-1, Interferon regulatory factors, medicine.drug
Abstract: International audience; Caspase‐4, the cytosolic LPS sensor, and gasdermin D, its downstream effector, constitute the non‐canonical inflammasome, which drives inflammatory responses during Gram‐negative bacterial infections. It remains unclear whether other proteins regulate cytosolic LPS sensing, particularly in human cells. Here, we conduct a genome‐wide CRISPR/Cas9 screen in a human monocyte cell line to identify genes controlling cytosolic LPS‐mediated pyroptosis. We find that the transcription factor, IRF2, is required for pyroptosis following cytosolic LPS delivery and functions by directly regulating caspase‐4 levels in human monocytes and iPSC‐derived monocytes. CASP4, GSDMD, and IRF2 are the only genes identified with high significance in this screen highlighting the simplicity of the non‐canonical inflammasome. Upon IFN‐γ priming, IRF1 induction compensates IRF2 deficiency, leading to robust caspase‐4 expression. Deficiency in IRF2 results in dampened inflammasome responses upon infection with Gram‐negative bacteria. This study emphasizes the central role of IRF family members as specific regulators of the non‐canonical inflammasome.
Published: 2019
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30. Type I Interferon Receptor Signaling Drives Selective Permissiveness of Astrocytes and Microglia to Measles Virus during Brain Infection

Author: Jeremy Charles Welsch, Denis Gerlier, Sébastien Dussurgey, Benjamin Charvet, Omran Allatif, Cyrille Mathieu, Branka Horvat, Noémie Aurine, Immunobiologie des infections virales – Immunobiology of Viral Infections (IbIV), 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)-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), SFR Biosciences, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie et pathogenèse virale (VPV), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, 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)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)
Subjects: Central Nervous System, Male, 0301 basic medicine, Permissiveness, Immunology, Central nervous system, Receptor, Interferon alpha-beta, Antiviral Agents, Hippocampus, Microbiology, Measles virus, Mice, 03 medical and health sciences, 0302 clinical medicine, Signaling Lymphocytic Activation Molecule Family Member 1, Downregulation and upregulation, Interferon, Virology, medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Neurons, biology, Microglia, Brain, medicine.disease, biology.organism_classification, 3. Good health, Astrogliosis, Oligodendroglia, 030104 developmental biology, medicine.anatomical_structure, Astrocytes, Insect Science, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cytokines, Pathogenesis and Immunity, Female, 030217 neurology & neurosurgery, Measles, Signal Transduction, medicine.drug, Astrocyte
Abstract: Fatal neurological syndromes can occur after measles virus (MeV) infection of the brain. The mechanisms controlling MeV spread within the central nervous system (CNS) remain poorly understood. We analyzed the role of type I interferon (IFN-I) receptor (IFNAR) signaling in the control of MeV infection in a murine model of brain infection. Using organotypic brain cultures (OBC) from wild-type and IFNAR-knockout (IFNAR(KO)) transgenic mice ubiquitously expressing the human SLAM (CD150) receptor, the heterogeneity of the permissiveness of different CNS cell types to MeV infection was characterized. In the absence of IFNAR signaling, MeV propagated significantly better in explant slices. In OBC from IFNAR-competent mice, while astrocytes and microglia were infected on the day of explant preparation, they became refractory to infection with time, in contrast to neurons and oligodendrocytes, which remained permissive to infection. This selective loss of permissiveness to MeV infection was not observed in IFNAR(KO) mouse OBC. Accordingly, the development of astrogliosis related to the OBC procedure was exacerbated in the presence of IFNAR signaling. In the hippocampus, this astrogliosis was characterized by a change in the astrocyte phenotype and by an increase of IFN-I transcripts. A proteome analysis showed the upregulation of 84 out of 111 secreted proteins. In the absence of IFNAR, only 27 secreted proteins were upregulated, and none of these were associated with antiviral activities. Our results highlight the essential role of the IFN-I response in astrogliosis and in the permissiveness of astrocytes and microglia that could control MeV propagation throughout the CNS. IMPORTANCE Measles virus (MeV) can infect the central nervous system (CNS), with dramatic consequences. The mechanisms controlling MeV invasion of the CNS remain ill-defined since most previous data were obtained from postmortem analysis. Here, we highlight for the first time the crucial role of the type I interferon (IFN-I) response not only in the control of CNS invasion but also in the early permissiveness of glial cells to measles virus infection.
Published: 2019
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31. Plasmacytoid Dendritic Cells and Infected Cells Form an Interferogenic Synapse Required for Antiviral Responses

Author: Marlène Dreux, Séverin Coléon, Lee Sherry, Elodie Décembre, Congcong Dong, Brian Webster, Sonia Assil, Omran Allatif, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CCSD, Accord Elsevier, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)
Subjects: Hepatitis C virus, [SDV]Life Sciences [q-bio], Endocytic cycle, Integrin, Hepacivirus, Dengue virus, medicine.disease_cause, Microbiology, Antiviral Agents, Virus, Cell Line, Synapse, 03 medical and health sciences, 0302 clinical medicine, Interferon, Virology, medicine, Cell Adhesion, Humans, Immunologic Factors, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, hemic and immune systems, TLR7, Dendritic Cells, Zika Virus, Dengue Virus, Intercellular Adhesion Molecule-1, Coculture Techniques, Immunity, Innate, Lymphocyte Function-Associated Antigen-1, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Toll-Like Receptor 7, Virus Diseases, Interferon Type I, biology.protein, Parasitology, 030217 neurology & neurosurgery, medicine.drug
Abstract: Type I interferon (IFN-I) is critical for antiviral defense, and plasmacytoid dendritic cells (pDCs) are a predominant source of IFN-I during virus infection. pDC-mediated antiviral responses are stimulated upon physical contact with infected cells, during which immunostimulatory viral RNA is transferred to pDCs, leading to IFN production via the nucleic acid sensor TLR7. Using dengue, hepatitis C, and Zika viruses, we demonstrate that the contact site of pDCs with infected cells is a specialized platform we term the interferogenic synapse, which enables viral RNA transfer and antiviral responses. This synapse is formed via αLβ2 integrin-ICAM-1 adhesion complexes and the recruitment of the actin network and endocytic machinery. TLR7 signaling in pDCs promotes interferogenic synapse establishment and provides feed-forward regulation, sustaining pDC contacts with infected cells. This interferogenic synapse may allow pDCs to scan infected cells and locally secrete IFN-I, thereby confining a potentially deleterious response.
Published: 2019
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32. Antiviral Response by Plasmacytoid Dendritic Cells via Interferogenic Synapse with Infected Cells

Author: Brian Webster, Omran Allatif, Séverin Coléon, Sonia Assil, Elodie Décembre, Marlène Dreux, and Lee Sherry
Subjects: hemic and immune systems, Biology, medicine.disease, Endocytosis, Dengue fever, Cell biology, Synapse, Interferon, medicine, Secretion, Receptor, Actin, Function (biology), medicine.drug
Abstract: SummaryType I interferon (IFN-I) is critical for protection against viral infections. Plasmacytoid dendritic cells (pDCs) massively produce IFN-I against viruses. Physical contacts are required for pDC-mediated sensing of cells infected by genetically distant viruses. How and why these contacts are established remains enigmatic. Using dengue, hepatitis C, zika viruses, we demonstrate that the pDC/infected cell interface is a specialized platform for viral immunostimulatory-RNA transfer, which we named interferogenic synapse and required for pDC-mediated antiviral response. This synapse is an exquisitely differentiated territory with polarized adhesion complexes and regulators of actin network and endocytosis. Toll-like receptor 7-induced signaling in pDCs promotes the interferogenic synapse establishment, thus providing a feed-forward regulation that sustains contacts with infected cells. We propose that the interferogenic synapse is crucial to pDC function as it allows scanning of infected cells to locally secrete IFN-I at the infection site, thereby confining a response potentially deleterious to the host.HighlightspDCs adhere to infected cells via αLβ2 integrin/ICAM-1Regulators of actin network and endocytosis polarize at contactTLR7-induced signaling potentiates pDC polarityInfected cells activate pDCs by interferogenic synapse
Published: 2018
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33. IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection

Author: Sacha Benaoudia, Sophia Djebali, Pierre Wallet, Angelina Provost, Pauline Basso, Igor Golovliov, Anders Sjöstedt, Etienne Meunier, Eric Faudry, Bénédicte F. Py, Fanny Michal, Omran Allatif, Brice Lagrange, Helena Lindgren, Amandine Mosnier, Amandine Martin, Petr Broz, Thomas Henry, Masahiro Yamamoto, Inflammasome, Infections bactériennes et autoinflammation, Inflammasome, Bacterial Infections and Autoinflammation (I2BA), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie de l'allergie cutanée et vaccination – Immunology of skin allergy and vaccination, Laboratory for Molecular Infection Medicine Sweden and Department of Clinical Microbiology, Pathogénie bactérienne et réponses cellulaires, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Immunité et lymphocytes cytotoxiques – Immunity and cytotoxic lymphocytes, Focal Area Infection Biology, Biozentrum, University of Basel (Unibas), Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), Osaka University [Osaka], Inflammasome NLRP3 – NLRP3 Inflammasome, Pathogenèse bactérienne et réponses cellulaires (PBRC), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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)-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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Inflammasomes, Fluorescent Antibody Technique, Apoptosis, medicine.disease_cause, Pathology and Laboratory Medicine, Inbred C57BL, Biochemistry, White Blood Cells, Mice, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Biology (General), Francisella, Francisella tularensis, Tularemia, Mice, Knockout, Immune System Proteins, Cell Death, Effector, Antimicrobials, Biochemistry and Molecular Biology, Drugs, Inflammasome, Flow Cytometry, 3. Good health, Cell biology, Bacterial Pathogens, Chemistry, Intracellular Pathogens, Cell Processes, Medical Microbiology, Gene Knockdown Techniques, Physical Sciences, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Cellular Types, Pathogens, medicine.drug, Research Article, QH301-705.5, Immune Cells, Knockout, Immunology, Immunoblotting, Enzyme-Linked Immunosorbent Assay, Biology, Microbiology, 03 medical and health sciences, AIM2, Interferon-gamma, Immune system, GTP-Binding Proteins, Virology, Microbial Control, Genetics, medicine, Animals, Francisella novicida, Molecular Biology, Microbial Pathogens, Pharmacology, Blood Cells, Bacteria, Animal, Intracellular parasite, Macrophages, Chemical Compounds, Organisms, Biology and Life Sciences, Proteins, Cell Biology, RC581-607, Iodides, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Disease Models, Antibacterials, Parasitology, Immunologic diseases. Allergy, Gram-Negative Bacterial Infections, Inflammasome complex, Biokemi och molekylärbiologi, 030215 immunology
Abstract: Guanylate binding proteins (GBPs) are interferon-inducible proteins involved in the cell-intrinsic immunity against numerous intracellular pathogens. The molecular mechanisms underlying the potent antibacterial activity of GBPs are still unclear. GBPs have been functionally linked to the NLRP3, the AIM2 and the caspase-11 inflammasomes. Two opposing models are currently proposed to explain the GBPs-inflammasome link: i) GBPs would target intracellular bacteria or bacteria-containing vacuoles to increase cytosolic PAMPs release ii) GBPs would directly facilitate inflammasome complex assembly. Using Francisella novicida infection, we investigated the functional interactions between GBPs and the inflammasome. GBPs, induced in a type I IFN-dependent manner, are required for the F. novicida-mediated AIM2-inflammasome pathway. Here, we demonstrate that GBPs action is not restricted to the AIM2 inflammasome, but controls in a hierarchical manner the activation of different inflammasomes complexes and apoptotic caspases. IFN-γ induces a quantitative switch in GBPs levels and redirects pyroptotic and apoptotic pathways under the control of GBPs. Furthermore, upon IFN-γ priming, F. novicida-infected macrophages restrict cytosolic bacterial replication in a GBP-dependent and inflammasome-independent manner. Finally, in a mouse model of tularemia, we demonstrate that the inflammasome and the GBPs are two key immune pathways functioning largely independently to control F. novicida infection. Altogether, our results indicate that GBPs are the master effectors of IFN-γ-mediated responses against F. novicida to control antibacterial immune responses in inflammasome-dependent and independent manners., Author summary The cell-intrinsic immunity is defined as the mechanisms allowing a host cell infected by an intracellular pathogen to mount effective immune mechanisms to detect and eliminate pathogens without any help from other immune cells. In infected macrophages, the Guanylate Binding Proteins (GBPs) are immune proteins, induced at low levels in a cell autonomous manner by endogenous type I IFN or at high levels following IFN-γ production by innate and adaptive lymphocytes. The antibacterial activity of GBPs has been recently tightly linked to the inflammasomes. Inflammasomes are innate immune complexes leading to inflammatory caspases activation and death of the infected cell. Francisella novicida, a bacterium replicating in the macrophage cytosol, is closely related to F. tularensis, the agent of tularemia and is used as a model to study cytosolic immunity. GBPs contribute to F. novicida lysis within the host cytosol leading to DNA release and AIM2 inflammasome activation. In addition to their regulation of the AIM2 inflammasome, we identified that GBPs also control several other pyroptotic and apoptotic pathways activated in a hierarchical manner. Furthermore, we demonstrate that IFN-γ priming extends GBPs anti-microbial responses from the inflammasome-dependent control of cell death to an inflammasome-independent control of cytosolic bacterial replication. Our results, validated in a mouse model of tularemia, thus segregate the antimicrobial activities of inflammasomes and GBPs as well as highlight GBPs as the master effectors of IFN-γ-mediated cytosolic immunity.
Published: 2017
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34. Silencing of natural transformation by an RNA chaperone and a multitarget small RNA

Author: Flora Peillard-Fiorente, Ayat R. Omar, Ross A. Edwards, Xavier Charpentier, Mark Glover, Andrew M. MacMillan, Laetitia Attaiech, Aïda Boughammoura, Omran Allatif, Céline Brochier-Armanet, Transfert de gène horizontal chez les bactéries pathogènes – Horizontal gene transfer in bacterial pathogens, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microbiologie, adaptation et pathogénie (MAP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Bioinformatique, phylogénie et génomique évolutive (BPGE), Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), BioInformatique et BioStatistiques (BIBS), University of Alberta, 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)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)
Subjects: 0301 basic medicine, DNA, Bacterial, Small RNA, Gene Transfer, Horizontal, 030106 microbiology, non-coding RNA, ProQ/FinO, Gene Transfer, Repressor, Biology, natural transformation, Regulon, Horizontal, Legionella pneumophila, Transformation, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Genetic, Models, Humans, Gene, Genetics, Multidisciplinary, Models, Genetic, Gene Expression Profiling, RNA chaperone, Bacterial, RNA, Gene Expression Regulation, Bacterial, DNA, Biological Sciences, Non-coding RNA, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Transformation (genetics), RNA, Bacterial, chemistry, Gene Expression Regulation, Horizontal gene transfer, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Transformation, Bacterial, Legionnaires' Disease
Abstract: International audience; A highly conserved DNA uptake system allows many bacteria to actively import and integrate exogenous DNA. This process, called natural transformation, represents a major mechanism of horizontal gene transfer (HGT) involved in the acquisition of virulence and antibiotic resistance determinants. Despite evidence of HGT and the high level of conservation of the genes coding the DNA uptake system, most bacterial species appear non-transformable under laboratory conditions. In naturally transformable species, the DNA uptake system is only expressed when bacteria enter a physiological state called competence, which develops under specific conditions. Here, we investigated the mechanism that controls expression of the DNA uptake system in the human pathogen Legionella pneumophila We found that a repressor of this system displays a conserved ProQ/FinO domain and interacts with a newly characterized trans-acting sRNA, RocR. Together, they target mRNAs of the genes coding the DNA uptake system to control natural transformation. This RNA-based silencing represents a previously unknown regulatory means to control this major mechanism of HGT. Importantly, these findings also show that chromosome-encoded ProQ/FinO domain-containing proteins can assist trans-acting sRNAs and that this class of RNA chaperones could play key roles in post-transcriptional gene regulation throughout bacterial species.
Published: 2016
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35. Jejunal T Cell Inflammation in Human Obesity Correlates with Decreased Enterocyte Insulin Signaling

Author: Aurelie Cotillard, Romain Remark, Karine Clément, Omran Allatif, Christine Poitou, Céline Osinski, Carla Mendes-Sá, Catherine Sautès-Fridman, Milena Monteiro-Sepulveda, Hélène Fohrer-Ting, Laurent Genser, Sébastien André, Sothea Touch, Armelle Leturque, Edwige-Ludiwyne Hubert, Kevin Garbin, Joan Tordjman, Edith Brot-Laroche, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Laboratoire de chimie Macromoléculaire (CNRS UMR 5076), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Sorbonne Université (SU), BioInformatique et BioStatistiques (BIBS), 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)-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 de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Innate Pharma, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Metabolisme et Differenciation Intestinale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), FOHRER-TING, Hélène, Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], 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), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), École pratique des hautes études (EPHE), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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)-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), and Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Physiology, medicine.medical_treatment, T-Lymphocytes, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 0302 clinical medicine, Insulin, Intestinal Mucosa, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Glucose Transporter Type 2, 0303 health sciences, biology, Middle Aged, medicine.anatomical_structure, Cytokine, Jejunum, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Female, medicine.symptom, Signal Transduction, Adult, medicine.medical_specialty, Enterocyte, CD8 Antigens, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Insulin resistance, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Obesity, Molecular Biology, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, 030304 developmental biology, Lamina propria, Lipid metabolism, Cell Biology, medicine.disease, Insulin receptor, Endocrinology, Enterocytes, Immunology, biology.protein, Insulin Resistance
Abstract: SummaryIn obesity, insulin resistance is linked to inflammation in several tissues. Although the gut is a very large lymphoid tissue, inflammation in the absorptive small intestine, the jejunum, where insulin regulates lipid and sugar absorption is unknown. We analyzed jejunal samples of 185 obese subjects stratified in three metabolic groups: without comorbidity, suffering from obesity-related comorbidity, and diabetic, versus 33 lean controls. Obesity increased both mucosa surface due to lower cell apoptosis and innate and adaptive immune cell populations. The preferential CD8αβ T cell location in epithelium over lamina propria appears a hallmark of obesity. Cytokine secretion by T cells from obese, but not lean, subjects blunted insulin signaling in enterocytes relevant to apical GLUT2 mislocation. Statistical links between T cell densities and BMI, NAFLD, or lipid metabolism suggest tissue crosstalk. Obesity triggers T-cell-mediated inflammation and enterocyte insulin resistance in the jejunum with potential broader systemic implications.
Published: 2015
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35 results on '"Omran, Allatif"'

1. Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2

2. Immunoprofiling of fresh HAM/TSP blood samples shows altered innate cell responsiveness.

3. Translation of SARS-CoV-2 gRNA Is Extremely Efficient and Competitive despite a High Degree of Secondary Structures and the Presence of an uORF

4. Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion

5. Combinatorial Expression of NK Cell Receptors Governs Cell Subset Reactivity and Effector Functions but Not Tumor Specificity

6. One-Year Follow-Up of Natural Killer Cell Activity in Multiple Myeloma Patients Treated With Adjuvant Lenalidomide Therapy

7. A third vaccine dose equalizes the levels of effectiveness and immunogenicity of heterologous or homologous COVID-19 vaccine regimens

8. Prior SARS-CoV-2 infection enhances and reshapes spike protein-specific memory induced by vaccination

9. Immunogenicity and efficacy of heterologous ChAdOx1–BNT162b2 vaccination

10. IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection.

11. High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors

12. Assessing mycoplasma contamination of cell cultures by qPCR using a set of universal primer pairs targeting a 1.5 kb fragment of 16S rRNA genes.

13. Immunoprofiling of fresh HAM/TSP blood samples shows altered innate cell responsiveness

14. A Dietary Supplement Containing Cinnamon, Chromium and Carnosine Decreases Fasting Plasma Glucose and Increases Lean Mass in Overweight or Obese Pre-Diabetic Subjects: A Randomized, Placebo-Controlled Trial.

15. Correction: A Dietary Supplement Containing Cinnamon, Chromium and Carnosine Decreases Fasting Plasma Glucose and Increases Lean Mass in Overweight or Obese Pre-Diabetic Subjects: A Randomized, Placebo-Controlled Trial.

16. Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2-infected cells

17. Polyclonal expansion of TCR Vb 21.3 + CD4 + and CD8 + T cells is a hallmark of multisystem inflammatory syndrome in children

18. Immunoprofiling of HTLV-1-infected individuals shows altered innate cell responsiveness in HAM/TSP patients

19. Polyclonal expansion of TCR Vbeta 21.3

20. Author response: Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion

21. Combinatorial Expression of NK Cell Receptors Governs Cell Subset Reactivity and Effector Functions But Not Tumor Specificity

22. DGINN, an automated and highly-flexible pipeline for the detection of genetic innovations on protein-coding genes

23. DGINN, an automated and highly-flexible pipeline for the detection of genetic innovations on protein-coding genes

24. A longitudinal study of SARS-CoV-2 infected patients shows high correlation between neutralizing antibodies and COVID-19 severity

25. Massive clonal expansion of polycytotoxic skin and blood CD8

26. Peripheral Natural Killer cells from chronic hepatitis B patients display molecular hallmarks of T cell exhaustion

27. Analyse moléculaire des patch-tests douteux aux médicaments

28. Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome

29. A genome‐wide screen identifies IRF2 as a key regulator of caspase‐4 in human cells

30. Type I Interferon Receptor Signaling Drives Selective Permissiveness of Astrocytes and Microglia to Measles Virus during Brain Infection

31. Plasmacytoid Dendritic Cells and Infected Cells Form an Interferogenic Synapse Required for Antiviral Responses

32. Antiviral Response by Plasmacytoid Dendritic Cells via Interferogenic Synapse with Infected Cells

33. IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection

34. Silencing of natural transformation by an RNA chaperone and a multitarget small RNA

35. Jejunal T Cell Inflammation in Human Obesity Correlates with Decreased Enterocyte Insulin Signaling

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35 results on '"Omran, Allatif"'

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