Search

Your search keyword '"Stéphane Rigaud"' showing total 5 results
Start Over Author "Stéphane Rigaud" Language english
5 results on '"Stéphane Rigaud"'

1. Antagonism of ALAS1 by the Measles Virus V protein contributes to degradation of the mitochondrial network and promotes interferon response.

Author

Pierre Khalfi, Rodolphe Suspène, Kyle A Raymond, Vincent Caval, Grégory Caignard, Noémie Berry, Valérie Thiers, Chantal Combredet, Claude Rufie, Stéphane Rigaud, Amine Ghozlane, Stevenn Volant, Anastassia V Komarova, Frédéric Tangy, and Jean-Pierre Vartanian

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

Viruses have evolved countless mechanisms to subvert and impair the host innate immune response. Measles virus (MeV), an enveloped, non-segmented, negative-strand RNA virus, alters the interferon response through different mechanisms, yet no viral protein has been described as directly targeting mitochondria. Among the crucial mitochondrial enzymes, 5'-aminolevulinate synthase (ALAS) is an enzyme that catalyzes the first step in heme biosynthesis, generating 5'-aminolevulinate from glycine and succinyl-CoA. In this work, we demonstrate that MeV impairs the mitochondrial network through the V protein, which antagonizes the mitochondrial enzyme ALAS1 and sequesters it to the cytosol. This re-localization of ALAS1 leads to a decrease in mitochondrial volume and impairment of its metabolic potential, a phenomenon not observed in MeV deficient for the V gene. This perturbation of the mitochondrial dynamics demonstrated both in culture and in infected IFNAR-/- hCD46 transgenic mice, causes the release of mitochondrial double-stranded DNA (mtDNA) in the cytosol. By performing subcellular fractionation post infection, we demonstrate that the most significant source of DNA in the cytosol is of mitochondrial origin. Released mtDNA is then recognized and transcribed by the DNA-dependent RNA polymerase III. The resulting double-stranded RNA intermediates will be captured by RIG-I, ultimately initiating type I interferon production. Deep sequencing analysis of cytosolic mtDNA editing divulged an APOBEC3A signature, primarily analyzed in the 5'TpCpG context. Finally, in a negative feedback loop, APOBEC3A an interferon inducible enzyme will orchestrate the catabolism of mitochondrial DNA, decrease cellular inflammation, and dampen the innate immune response.

Published
2023
Full Text
View/download PDF

2. SARS-CoV-2 infection induces the dedifferentiation of multiciliated cells and impairs mucociliary clearance

Author

Rémy Robinot, Mathieu Hubert, Guilherme Dias de Melo, Françoise Lazarini, Timothée Bruel, Nikaïa Smith, Sylvain Levallois, Florence Larrous, Julien Fernandes, Stacy Gellenoncourt, Stéphane Rigaud, Olivier Gorgette, Catherine Thouvenot, Céline Trébeau, Adeline Mallet, Guillaume Duménil, Samy Gobaa, Raphaël Etournay, Pierre-Marie Lledo, Marc Lecuit, Hervé Bourhy, Darragh Duffy, Vincent Michel, Olivier Schwartz, and Lisa A. Chakrabarti

Subjects
Science
Abstract

SARS-CoV-2 infection damages the airways. Here the authors show that SARS-CoV-2 infection induces the rapid loss of airway motile cilia, resulting in altered cilia clearance function. Cilia loss is preceded by reduced expression of the ciliogenesis regulator Foxj1.

Published
2021
Full Text
View/download PDF

3. Herpes Simplex Virus Type 1 Infection Disturbs the Mitochondrial Network, Leading to Type I Interferon Production through the RNA Polymerase III/RIG-I Pathway

Author

Noémie Berry, Rodolphe Suspène, Vincent Caval, Pierre Khalfi, Guillaume Beauclair, Stéphane Rigaud, Hervé Blanc, Marco Vignuzzi, Simon Wain-Hobson, and Jean-Pierre Vartanian

Subjects
HSV-1, mitochondria, innate immunity, cytidine deaminase, APOBEC3A, herpes simplex virus, Microbiology, QR1-502
Abstract

ABSTRACT Viruses have evolved a plethora of mechanisms to impair host innate immune responses. Herpes simplex virus type 1 (HSV-1), a double-stranded linear DNA virus, impairs the mitochondrial network and dynamics predominantly through the UL12.5 gene. We demonstrated that HSV-1 infection induced a remodeling of mitochondrial shape, resulting in a fragmentation of the mitochondria associated with a decrease in their volume and an increase in their sphericity. This damage leads to the release of mitochondrial DNA (mtDNA) to the cytosol. By generating a stable THP-1 cell line expressing the DNase I-mCherry fusion protein and a THP-1 cell line specifically depleted of mtDNA upon ethidium bromide treatment, we showed that cytosolic mtDNA contributes to type I interferon and APOBEC3A upregulation. This was confirmed by using an HSV-1 strain (KOS37 UL98-SPA) with a deletion of the UL12.5 gene that impaired its ability to induce mtDNA stress. Furthermore, by using an inhibitor of RNA polymerase III, we demonstrated that upon HSV-1 infection, cytosolic mtDNA enhanced type I interferon induction through the RNA polymerase III/RIG-I pathway. APOBEC3A was in turn induced by interferon. Deep sequencing analyses of cytosolic mtDNA mutations revealed an APOBEC3A signature predominantly in the 5′TpCpG context. These data demonstrate that upon HSV-1 infection, the mitochondrial network is disrupted, leading to the release of mtDNA and ultimately to its catabolism through APOBEC3-induced mutations. IMPORTANCE Herpes simplex virus 1 (HSV-1) impairs the mitochondrial network through the viral protein UL12.5. This leads to the fusion of mitochondria and simultaneous release of mitochondrial DNA (mtDNA) in a mouse model. We have shown that released mtDNA is recognized as a danger signal, capable of stimulating signaling pathways and inducing the production of proinflammatory cytokines. The expression of the human cytidine deaminase APOBEC3A is highly upregulated by interferon responses. This enzyme catalyzes the deamination of cytidine to uridine in single-stranded DNA substrates, resulting in the catabolism of edited DNA. Using human cell lines deprived of mtDNA and viral strains deficient in UL12, we demonstrated the implication of mtDNA in the production of interferon and APOBEC3A expression during viral infection. We have shown that HSV-1 induces mitochondrial network fragmentation in a human model and confirmed the implication of RNA polymerase III/RIG-I signaling in the capture of cytosolic mtDNA.

Published
2021
Full Text
View/download PDF

4. Neutrophils degranulate GAG-containing proteoglycofili, which block Shigella growth and degrade virulence factors

Author

Antonin C André, Marina Valente Barroso, Jurate Skerniskyte, Mélina Siegwald, Vanessa Paul, Lorine Debande, Caroline Ridley, Isabelle Svahn, Stéphane Rigaud, Jean-Yves Tinevez, Romain R Vivès, Philippe J Sansonetti, David J Thornton, Benoit S Marteyn, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Paris Cité (UPCité), University of Manchester [Manchester], Bordeaux Imaging Center (BIC), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagopole (CITECH), Institut Pasteur [Paris] (IP), CEA Grenoble (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), Réseau International des Instituts Pasteur (RIIP), Institut d’Etudes Avancées de l’Université de Strasbourg - Institute for Advanced Study (USIAS), Université de Strasbourg (UNISTRA), Pathogénèse des Infections vasculaires / Pathogenesis of Vascular Infections, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Tinevez, Jean-Yves

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract

Summary paragraphNeutrophil degranulation plays a central role in their ability to kill pathogens but also to stimulate other immune cells1–3. Here we show that neutrophil degranulation, induced in hypoxia or upon Shigella infection in vitro and in vivo, leads to the release of polymers called neutrophil Proteoglycofili (PGF). PGF are mainly composed of granular proteins (myeloperoxidase, elastase, lactoferrin, cathelicidin, albumin) pre-stored in various types of granules, and chondroitin sulfate. PGF individual fibers have a diameter of 43.9 ± 20.3 nm and. They secreted by viable neutrophils and do not contain DNA, as opposed to NETs which contains also granular proteins, chondroitin sulfate in addition to chromatin, released upon neutrophil disintegration and cell death.We demonstrated that PGF block the growth of Shigella and other bacteria and degrade Shigella virulence factors. The degradation of the chondroitin sulfate polymers with testes hyaluronidases destabilizes PGF ultrastructure and abolishes its antimicrobial activity. Our results provide novel insights in the neutrophil degranulation process and open new doors for the investigation of PGF contribution to cytokines concentration gradient formation and adaptive immune cells activation. Further investigations are required to better appreciate the importance of this “sterile blaster” in infectious or inflammatory diseases.

Published
2022

5. SARS-CoV-2 infection damages airway motile cilia and impairs mucociliary clearance

Author

Sylvain Levallois, Guillaume Duménil, Stéphane Rigaud, Françoise Lazarini, Olivier Gorgette, Lisa A. Chakrabarti, Rémy Robinot, Guilherme D. Melo, Julien Fernandes, Céline Trébeau, Pierre-Marie Lledo, Hervé Bourhy, Raphaël Etournay, Olivier Schwartz, Stacy Gellenoncourt, Samy Gobaa, Timothée Bruel, Florence Larrous, Mathieu Hubert, Marc Lecuit, Nikaïa Smith, Catherine Thouvenot, Darragh Duffy, Adeline Mallet, Vincent Michel, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris] (IP), Perception et Mémoire / Perception and Memory, Immunologie Translationnelle - Translational Immunology lab, Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Hub d'analyse d'images - Image Analysis Hub (Platform) (IAH), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut de l'Audition [Paris] (IDA), Plateforme technologique Biomatériaux et Microfluidique - Biomaterials and Microfluidics technologic Platform, Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by : Institut Pasteur TASK FORCE SARS COV2 (Tropicoro project), DIM ELICIT Region Ile-de-France, and ANRS (L.A.C.), the Vaccine Research Institute (ANR-10-LABX-77), ANRS, Labex IBEID (ANR-10-LABX-62-IBEID), 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro-Immuno' ANR-14-CE14- 0015-01, the Gilead HIV cure program, ANR/FRM Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR (O.S.), Institut Pasteur TASK FORCE SARS COV2 and ANR Flash Covid CoVarImm (D.D.), Institut Pasteur TASK FORCE SARS COV2 (Neuro-Covid project) (H.B.). The Lledo’s lab is supported by the life insurance company 'AG2R-La-Mondiale'. The UtechS Photonic BioImaging (Imagopole) and the UtechS Ultrastructural BioImaging (UBI) are supported by the French National Research Agency (France BioImaging, ANR-10–INSB–04, Investments for the Future). R.R. is the recipient of a Sidaction fellowship, N.S. of a Pasteur-Roux Cantarini fellowship, and St.G. of a MESR/Ecole Doctorale B3MI, Paris 7 University fellowship. S.L. is supported by FRM (fellowship ECO201906009119) and by 'Ecole Doctorale FIRE – Programme Bettencourt'., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), ANR-20-COVI-0053,CoVarImm,Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence(2020), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute (VRI), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]

Subjects
Axoneme, 0303 health sciences, Tight junction, Mucociliary clearance, Cilium, Biology, respiratory system, 3. Good health, Cell biology, respiratory tract diseases, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Parenchyma, Motile cilium, medicine, Basal body, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030304 developmental biology, Respiratory tract
Abstract

Understanding how SARS-CoV-2 spreads within the respiratory tract is important to define the parameters controlling the severity of COVID-19. We examined the functional and structural consequences of SARS-CoV-2 infection in a reconstituted human bronchial epithelium model. SARS-CoV-2 replication caused a transient decrease in epithelial barrier function and disruption of tight junctions, though viral particle crossing remained limited. Rather, SARS-CoV-2 replication led to a rapid loss of the ciliary layer, characterized at the ultrastructural level by axoneme loss and misorientation of remaining basal bodies. The motile cilia function was compromised, as measured in a mucociliary clearance assay. Epithelial defense mechanisms, including basal cell mobilization and interferon-lambda induction, ramped up only after the initiation of cilia damage. Analysis of SARS-CoV-2 infection in Syrian hamsters further demonstrated the loss of motile ciliain vivo. This study identifies cilia damage as a pathogenic mechanism that could facilitate SARS-CoV-2 spread to the deeper lung parenchyma.

Published
2021

Catalog

Books, media, physical & digital resources
See catalog results