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1. Adhesion to nanofibers drives cell membrane remodeling through one-dimensional wetting

Author

Charles-Orszag, Arthur, Tsai, Feng-Ching, Bonazzi, Daria, Manriquez, Valeria, Sachse, Martin, Mallet, Adeline, Salles, Audrey, Melican, Keira, Staneva, Ralitza, Bertin, Aurélie, Millien, Corinne, Goussard, Sylvie, Lafaye, Pierre, Shorte, Spencer, Piel, Matthieu, Krijnse-Locker, Jacomine, Brochard-Wyart, Françoise, Bassereau, Patricia, Duménil, Guillaume, 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 Descartes - Paris 5 (UPD5), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Microscopie ultrastructurale - Ultrapole (CITECH), Institut Pasteur [Paris] (IP), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ingénierie des Anticorps (plate-forme) - Antibody Engineering (Platform), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pierre-Gilles de Gennes pour la Microfluidique, Institut Curie [Paris], This work was supported by the French ministry for research and higher education (ACO), the Integrative Biology of Emerging Infectious Diseases (IBEID) laboratory of excellence (GD) and the VIP European Research Council starting grant (GD). We gratefully acknowledge the Imagopole—Citech of Institut Pasteur (Paris, France) as well as the France–BioImaging infrastructure network supported by the French National Research Agency (ANR-10–INSB–04, Investments for the Future), and the Région Ile-de-France (program Domaine d’Intérêt Majeur-Malinf) for the use of the Zeiss LSM 780 Elyra PS1 microscope and the Zeiss Auriga scanning electron microscope. The authors greatly acknowledge the Cell and Tissue Imaging (PICT-IBiSA), Institut Curie, member of the French National Research Infrastructure France-BioImaging (ANR10-INBS-04), and the PICT-IBiSA Institut Curie (Paris, France). This work was supported by Institut Curie, Fondation pour la Recherche Médicale (FRM FDT20170437130) and Ecole Doctorale Frontières du Vivant (FdV)–Programme Bettencourt (RS), ERC StG grant STARLIN (DMV), Centre National de la Recherche Scientifique (CNRS), and P. B. and F.B.-W. belong to the CNRS consortium CellTiss, to the Labex CelTisPhyBio (ANR-11-LABX0038) and to Paris Sciences et Lettres (). F.C.T. was funded by the EMBO Long-Term fellowship (ALTF 1527-2014) and Marie Curie actions (H2020-MSCA-IF-2014, project membrane-ezrin-actin)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-11-LABX-0038,CelTisPhyBio,Des cellules aux tissus: au croisement de la Physique et de la Biologie(2011), European Project: 656442,H2020,H2020-MSCA-IF-2014,membrane-ezrin-actin(2016), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Physico-Chimie-Curie (PCC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Lafaye, pierre, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Des cellules aux tissus: au croisement de la Physique et de la Biologie - - CelTisPhyBio2011 - ANR-11-LABX-0038 - LABX - VALID, Membrane-ezrin-actin interactions mediated by ezrin binding proteins in reconstituted systems - membrane-ezrin-actin - - H20202016-01-01 - 2018-01-01 - 656442 - VALID, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Science, Cell Membrane, Nanofibers, Mice, SCID, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Neisseria meningitidis, Models, Biological, Bacterial Adhesion, Article, Liposomes, Human Umbilical Vein Endothelial Cells, Wettability, Animals, Humans, lcsh:Q, Cell Surface Extensions, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, lcsh:Science
Abstract

The shape of cellular membranes is highly regulated by a set of conserved mechanisms that can be manipulated by bacterial pathogens to infect cells. Remodeling of the plasma membrane of endothelial cells by the bacterium Neisseria meningitidis is thought to be essential during the blood phase of meningococcal infection, but the underlying mechanisms are unclear. Here we show that plasma membrane remodeling occurs independently of F-actin, along meningococcal type IV pili fibers, by a physical mechanism that we term ‘one-dimensional’ membrane wetting. We provide a theoretical model that describes the physical basis of one-dimensional wetting and show that this mechanism occurs in model membranes interacting with nanofibers, and in human cells interacting with extracellular matrix meshworks. We propose one-dimensional wetting as a new general principle driving the interaction of cells with their environment at the nanoscale that is diverted by meningococci during infection., Meningococci remodel the plasma membrane of host cells during infection. Here, Charles-Orszag et al. show that plasma membrane remodeling occurs independently of F-actin, along meningococcal type IV pili fibers, by a physical mechanism that they term ‘one-dimensional’ membrane wetting.

Published
2018
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2. Innate Immune Signals Induce Anterograde Endosome Transport Promoting MHC Class I Cross-Presentation

Author

Beaune, Gregory, Blanch-Mercader, Carles, Douezan, Stephane, Dumond, Julien, Gonzalez-Rodriguez, David, Cuvelier, Damien, Ondarçuhu, Thierry, Sens, Pierre, Dufour, Sylvie, Murrell, Michael, Charles-Orszag, Arthur, Tsai, Feng-Ching, Bonazzi, Daria, Manriquez, Valeria, Sachse, Martin, Mallet, Adeline, Salles, Audrey, Melican, Keira, Staneva, Ralitza, Bertin, Aurélie, Millien, Corinne, Goussard, Sylvie, Lafaye, Pierre, Shorte, Spencer, Piel, Matthieu, Krijnse-Locker, Jacomine, Brochard-Wyart, Françoise, Bassereau, Patricia, Duménil, Guillaume, Weimershaus, Mirjana, Mauvais, Francois-Xavier, Saveanu, Loredana, Adiko, Cézaire, Babdor, Joel, Abramova, Anastasia, Montealegre, Sebastian, Lawand, Myriam, Evnouchidou, Irini, Huber, Katharina Julia, Chadt, Alexandra, Zwick, Markus, Vargas, Pablo, Dussiot, Michaël, Lennon-Dumenil, Ana Maria, Brocker, Thomas, Al-Hasani, Hadi, Van Endert, Peter, National Institute for Materials Science (NIMS), Physico-Chimie-Curie (PCC), Institut Curie-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre d'élaboration de matériaux et d'études structurales (CEMES), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Biologie des Organismes et Ecosystèmes Aquatiques (BOREA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Muséum national d'Histoire naturelle (MNHN)-Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Pathogénèse des Infections vasculaires, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Microscopie ultrastructurale (plate-forme), Institut Pasteur [Paris], Imagopole (CITECH), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Neuroscience, Karolinska Institutet [Stockholm], Institut Curie, SAFT [Bordeaux], Société des accumulateurs fixes et de traction (SAFT), Ingénierie des Anticorps (plate-forme) - Antibody Engineering (Platform), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Compartimentation et dynamique cellulaires (CDC), Microscopie ultrastructurale - Ultrapole (CITECH), Diabète de Type 1 : mécanismes et traitements immunologiques, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-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 Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-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), Immunité et cancer, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Endosome, Antigen presentation, Fc receptor, Kinesins, Endosomes, Receptors, Fc, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Microtubules, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Mice, Cross-Priming, Phagosomes, Animals, lcsh:QH301-705.5, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Phagosome, Innate immune system, biology, Chemistry, Histocompatibility Antigens Class I, Cross-presentation, Dendritic cell, Immunity, Innate, Cell biology, Toll-Like Receptor 4, Protein Transport, 030104 developmental biology, lcsh:Biology (General), rab GTP-Binding Proteins, biology.protein, Kinesin, Female
Abstract

Summary: Both cross-presentation of antigens by dendritic cells, a key pathway triggering T cell immunity and immune tolerance, and survival of several pathogens residing in intracellular vacuoles are intimately linked to delayed maturation of vesicles containing internalized antigens and microbes. However, how early endosome or phagosome identity is maintained is incompletely understood. We show that Toll-like receptor 4 (TLR4) and Fc receptor ligation induces interaction of the GTPase Rab14 with the kinesin KIF16b mediating plus-end-directed microtubule transport of endosomes. As a result, Rab14 recruitment to phagosomes delays their maturation and killing of an internalized pathogen. Enhancing anterograde transport by overexpressing Rab14, promoting the GTP-bound Rab14 state, or inhibiting retrograde transport upregulates cross-presentation. Conversely, reducing Rab14 expression, destabilizing Rab14 endosomes, and inhibiting anterograde microtubule transport by Kif16b knockdown compromise cross-presentation. Therefore, regulation of early endosome trafficking by innate immune signals is a critical parameter in cross-presentation by dendritic cells. : Weimershaus et al. identify a molecular complex that controls the intracellular trafficking along microtubules of antigens internalized by dendritic cells. They show that this trafficking is regulated by innate immune signals and regulates presentation of internalized antigens to T lymphocytes. Keywords: antigen presentation, cross-presentation, dendritic cell, MHC class I, endosome, small GTPase, kinesin, Rab14

Published
2018
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3. Chikungunya Virus Replication in Salivary Glands of the Mosquito Aedes albopictus

Author

Christine Schmitt, Jacomine Krijnse Locker, Anubis Vega-Rúa, Isabelle Bonne, Anna-Bella Failloux, Arbovirus et Insectes Vecteurs - Arboviruses and Insect Vectors, Institut Pasteur [Paris], Microscopie ultrastructurale - Ultrapole (CITECH), This study was funded by the Institut Pasteur, the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant No. ANR-10-LABX-62-IBEID). AVR was supported by the French Ministry of Superior Education and Research., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and Institut Pasteur [Paris] (IP)

Subjects
Saliva, replication, Aedes albopictus, viruses, salivary glands, lcsh:QR1-502, budding, MESH: Chikungunya virus/physiology, medicine.disease_cause, Virus Replication, Arbovirus, Virus, lcsh:Microbiology, MESH: Chikungunya virus/growth & development, Microscopy, Electron, Transmission, stomatognathic system, Aedes, Virology, parasitic diseases, transmission electron microscopy, medicine, Animals, MESH: Animals, Chikungunya, biology, MESH: Aedes/virology, Brief Report, fungi, MESH: Virus Replication, Virion, virus diseases, Midgut, MESH: Salivary Glands/virology, biology.organism_classification, medicine.disease, 3. Good health, Infectious Diseases, Viral replication, MESH: Virion/ultrastructure, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Microscopy, Electron, Transmission, Female, Chikungunya virus, MESH: Female
Abstract

International audience; Chikungunya virus (CHIKV) is an emerging arbovirus transmitted to humans by mosquitoes such as Aedes albopictus. To be transmitted, CHIKV must replicate in the mosquito midgut, then disseminate in the hemocele and infect the salivary glands before being released in saliva. We have developed a standardized protocol to visualize viral particles in the mosquito salivary glands using transmission electron microscopy. Here we provide direct evidence for CHIKV replication and storage in Ae. albopictus salivary glands.

Published
2017
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4. A Large Collection of Novel Nematode-Infecting Microsporidia and Their Diverse Interactions with Caenorhabditis elegans and Other Related Nematodes

Author

Zhang, Gaotian, Sachse, Martin, Prevost, Marie-Christine, Luallen, Robert J., Troemel, Emily R., Félix, Marie-Anne, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microscopie ultrastructurale - Ultrapole (CITECH), Institut Pasteur [Paris] (IP), University of California [San Diego] (UC San Diego), University of California (UC), This work was supported by: Ecole Normale Supérieure, Centre National de la Recherche Scientifique, Inserm, Fondation pour la Recherche Médicale DEQ20150331704, Fondation Bettencourt-Schueller Coup d'Elan 2011, Fellowship from the China Scholarship Council, National Science Foundation Graduate Research fellowship, NIH R01GM114139 and Burroughs Wellcome Fund fellowship, and National Science Foundation Graduate Research Opportunities Worldwide. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], University of California, and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)

Subjects
Nematoda, Cell Membranes, Pathogenesis, Pathology and Laboratory Medicine, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Polymerase Chain Reaction, Microsporidiosis, Medicine and Health Sciences, Nematode Infections, lcsh:QH301-705.5, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Phylogeny, Fungal Pathogens, [SDV.BA]Life Sciences [q-bio]/Animal biology, Animal Models, Experimental Organism Systems, Medical Microbiology, Host-Pathogen Interactions, Pathogens, Anatomy, Cellular Structures and Organelles, Research Article, lcsh:Immunologic diseases. Allergy, Mycology, [SDV.BID]Life Sciences [q-bio]/Biodiversity, Research and Analysis Methods, Microbiology, Model Organisms, Microscopy, Electron, Transmission, Virology, parasitic diseases, Parasitic Diseases, Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Caenorhabditis elegans, Microbial Pathogens, Host Cells, fungi, Organisms, Biology and Life Sciences, Correction, Cell Biology, Invertebrates, Gastrointestinal Tract, lcsh:Biology (General), Microsporidia, Caenorhabditis, lcsh:RC581-607, Digestive System, Viral Transmission and Infection
Abstract

Microsporidia are fungi-related intracellular pathogens that may infect virtually all animals, but are poorly understood. The nematode Caenorhabditis elegans has recently become a model host for studying microsporidia through the identification of its natural microsporidian pathogen Nematocida parisii. However, it was unclear how widespread and diverse microsporidia infections are in C. elegans or other related nematodes in the wild. Here we describe the isolation and culture of 47 nematodes with microsporidian infections. N. parisii is found to be the most common microsporidia infecting C. elegans in the wild. In addition, we further describe and name six new species in the Nematocida genus. Our sampling and phylogenetic analysis further identify two subclades that are genetically distinct from Nematocida, and we name them Enteropsectra and Pancytospora. Interestingly, unlike Nematocida, these two genera belong to the main clade of microsporidia that includes human pathogens. All of these microsporidia are horizontally transmitted and most specifically infect intestinal cells, except Pancytospora epiphaga that replicates mostly in the epidermis of its Caenorhabditis host. At the subcellular level in the infected host cell, spores of the novel genus Enteropsectra show a characteristic apical distribution and exit via budding off of the plasma membrane, instead of exiting via exocytosis as spores of Nematocida. Host specificity is broad for some microsporidia, narrow for others: indeed, some microsporidia can infect Oscheius tipulae but not its sister species Oscheius sp. 3, and conversely some microsporidia found infecting Oscheius sp. 3 do not infect O. tipulae. We also show that N. ausubeli fails to strongly induce in C. elegans the transcription of genes that are induced by other Nematocida species, suggesting it has evolved mechanisms to prevent induction of this host response. Altogether, these newly isolated species illustrate the diversity and ubiquity of microsporidian infections in nematodes, and provide a rich resource to investigate host-parasite coevolution in tractable nematode hosts., Author Summary Microsporidia are microbial parasites that live inside their host cells and can cause disease in humans and many other animals. The small nematode worm Caenorhabditis elegans has recently become a convenient model host for studying microsporidian infections. In this work, we sample Caenorhabditis and other small nematodes and 47 associated microsporidian strains from the wild. We characterize the parasites for their position in the evolutionary tree of microsporidia and for their lifecycle and morphology. We find several new species and genera, especially some that are distantly related to the previously known Nematocida parisii and instead closely related to human pathogens. We find that some of these species have a narrow host range. We studied two species in detail using electron microscopy and uncover a new likely mode of exit from the host cell, by budding off the host cell plasma membrane rather than by fusion of a vesicle to the plasma membrane as in N. parisii. We also find a new species that infects the epidermis and muscles of Caenorhabditis rather than the host intestinal cells and is closely related to human pathogens. Finally, we find that one Nematocida species fails to elicit the same host response that other Nematocida species do. These new microsporidia open up many windows into microsporidia biology and opportunities to investigate host-parasite coevolution in the C. elegans system.

Published
2016
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5. Biosynthesis of cell wall mannan in the conidium and the mycelium of Aspergillus fumigatus

Author

Henry, Christine, Fontaine, Thierry, Heddergott, Christoph, Robinet, Pauline, Aimanianda, Vishukumar, Beau, Remi, Beauvais, Anne, Mouyna, Isabelle, Prevost, Marie-Christine, Fekkar, Arnaud, Zhao, Yanan, Perlin, David, Latgé, Jean-Paul, Aspergillus, Institut Pasteur [Paris], Microscopie ultrastructurale - Ultrapole (CITECH), Service de parasitologie - mycologie [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), Rutgers, The State University of New Jersey [New Brunswick] (RU), Rutgers University System (Rutgers), This work was partly supported by grants of Aviesan, FRM, and Labex IBEID., Institut Pasteur [Paris] (IP), CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Mycelium, Virulence, Aspergillus fumigatus, Galactose, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Spores, Fungal, bacterial infections and mycoses, Mannosyltransferases, carbohydrates (lipids), Fungal Proteins, Mannans, Mice, Cell Wall, Gene Expression Regulation, Fungal, Host-Pathogen Interactions, Carbohydrate Conformation, Animals, Aspergillosis, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], skin and connective tissue diseases, Mannose, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Gene Deletion
Abstract

International audience; The galactomannan is a major cell wall molecule of Aspergillus fumigatus. This molecule is composed of a linear mannan with a repeating unit composed of four α1,6 and α1,2 linked mannose with side chains of galactofuran. To obtain a better understanding of the mannan biosynthesis in A. fumigatus, it was decided to undertake the successive deletion of the 11 genes which are putative orthologs of the mannosyltransferases responsible for establishing α1,6 and α1,2 mannose linkages in yeast. These deletions did not lead to a reduction of the mannan content of the cell wall of the mycelium of A. fumigatus. In contrast, the mannan content of the conidial cell wall was reduced and this reduction was associated with a partial disorganization of the cell wall leading to defects in conidial survival both in vitro and in vivo.

Published
2016
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6. Differential identity of Filopodia and Tunneling Nanotubes revealed by the opposite functions of actin regulatory complexes

Author

Andrea Disanza, Chiara Zurzolo, Giorgio Scita, Esthel Pénard, Diégo Cordero Cervantes, Elise Delage, Christine Schmitt, Sylvie Syan, Trafic membranaire et Pathogénèse, Institut Pasteur [Paris], Microscopie ultrastructurale - Ultrapole (CITECH), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Università degli Studi di Milano [Milano] (UNIMI), We gratefully acknowledge the kind financial support of the Institut Pasteur (Paris), the France–BioImaging infrastructure network supported by the French National Research Agency (ANR-10–INSB–04, Investments for the future), and the Région Ile-de-France (program DIM-Malinf ). We thank Dr. Jean-Yves Tinevez and Dr. Audrey Salles from Imagopole at Institut Pasteur for their help with microscopy imaging. We thank Dr. Sophie Novault from the Flow Cytometry Platform at Institut Pasteur for her help with flow cytometry experiments. We thank Dr. Fabrice De Chaumont from the Bioimage Analysis Unit at Institut Pasteur for his help with the software: ICY. E.D. is a recipient of the Bourse Carnot-Pasteur Maladies Infectieuses and the Bourse Pasteur-Roux, Institut Pasteur. This work is supported by research grants from the Agence Nationale de la Recherche (ANR-14-JPCD-0002-01 and ANR-16-CE16-0019-Neurotunn), AIC RECH COLLECT CYANOBAC, and Equipe FRM (Fondation Recherche Médicale) 2014 (DEQ20140329557) to C.Z., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-14-JPCD-0002,Neutargets,Targeting the propagation of pathogenic protein assemblies in neurodegenerative disease(2014), ANR-16-CE16-0019,Neurotunn,Role des nanotubes membranaires dans la propagation d'agrégats protéiques impliqués dans les maladie neurodégénératives(2016), Institut Pasteur [Paris] (IP), Università degli Studi di Milano = University of Milan (UNIMI), Delage, E., Cervantes, D. C., Penard, E., Schmitt, C., Syan, S., Disanza, A., Scita, G., and Zurzolo, C.

Subjects
0301 basic medicine, Cell signaling, Green Fluorescent Proteins, Nerve Tissue Proteins, CDC42, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, macromolecular substances, Cell Communication, Biology, Endocytosis, Green Fluorescent Protein, Article, EPS8, 03 medical and health sciences, Mice, Animals, Pseudopodia, cdc42 GTP-Binding Protein, Actin, Adaptor Proteins, Signal Transducing, Neurons, Multidisciplinary, Nanotubes, 030102 biochemistry & molecular biology, Endocytosi, Animal, Cell Membrane, Microfilament Proteins, Signal transducing adaptor protein, Brain, Microfilament Protein, Neuron, Phosphoproteins, Actins, Cell biology, Nanotube, Actin Cytoskeleton, 030104 developmental biology, Cell Adhesion Molecule, Phosphoprotein, Nerve Tissue Protein, Microscopy, Electron, Scanning, Filopodia, Cell Adhesion Molecules, Intracellular
Abstract

Tunneling Nanotubes (TNTs) are actin enriched filopodia-like protrusions that play a pivotal role in long-range intercellular communication. Different pathogens use TNT-like structures as “freeways” to propagate across cells. TNTs are also implicated in cancer and neurodegenerative diseases, making them promising therapeutic targets. Understanding the mechanism of their formation, and their relation with filopodia is of fundamental importance to uncover their physiological function, particularly since filopodia, differently from TNTs, are not able to mediate transfer of cargo between distant cells. Here we studied different regulatory complexes of actin, which play a role in the formation of both these structures. We demonstrate that the filopodia-promoting CDC42/IRSp53/VASP network negatively regulates TNT formation and impairs TNT-mediated intercellular vesicle transfer. Conversely, elevation of Eps8, an actin regulatory protein that inhibits the extension of filopodia in neurons, increases TNT formation. Notably, Eps8-mediated TNT induction requires Eps8 bundling but not its capping activity. Thus, despite their structural similarities, filopodia and TNTs form through distinct molecular mechanisms. Our results further suggest that a switch in the molecular composition in common actin regulatory complexes is critical in driving the formation of either type of membrane protrusion.

Published
2016
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7. Analysis of a Spontaneous Non-Motile and Avirulent Mutant Shows That FliM Is Required for Full Endoflagella Assembly in Leptospira interrogans

Author

Célia Fontana, Mathieu Picardeau, Nadia Benaroudj, Nathalie Michele Cachet, Olivier Gorgette, David Gasparini, Natalia Bomchil, Ambroise Lambert, Biologie des Spirochètes / Biology of Spirochetes, Institut Pasteur [Paris], Laboratoire Lyon Gerland, MERIAL, Centre de Recherche Clinique de Saint Vulbas, Microscopie ultrastructurale - Ultrapole (CITECH), This work was funded by the Institut Pasteur (http://www.pasteur.fr), FUI 14 (Fonds Unique Interministériel) 'COVALEPT', BPI France (http://www.bpifrance.fr/), Association Nationale de la Recherche et de la Technologie (http://www.anrt.asso.fr/), and Merial SAS France (http://www.merial.com). The funder provided support in the form of salaries for authors [CF, DG, NC, N. Benaroudj, MP, N. Bomchil, OG, AL] and research materials, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript., and Institut Pasteur [Paris] (IP)

Subjects
0301 basic medicine, lcsh:Medicine, Pathology and Laboratory Medicine, Cell morphology, Biochemistry, Medicine and Health Sciences, lcsh:Science, Leptospira, Mammals, MESH: Gene Expression Regulation, Bacterial, MESH: Genetic Complementation Test, Multidisciplinary, Virulence, biology, Bacterial Pathogens, 3. Good health, MESH: Leptospira interrogans/ultrastructure, Leptospira Interrogans, Cell Motility, MESH: Leptospira interrogans/physiology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Flagella, Medical Microbiology, Vertebrates, Hamsters, Cellular Structures and Organelles, Pathogens, Leptospira interrogans, Research Article, Pathogen Motility, MESH: Mutation, Virulence Factors, Motor Proteins, 030106 microbiology, Motility, Flagellum, MESH: Bacterial Proteins/genetics, Microbiology, Rodents, Motor protein, 03 medical and health sciences, Bacterial Proteins, Molecular Motors, Animals, MESH: Virulence/genetics, Microbial Pathogens, [SDV.GEN]Life Sciences [q-bio]/Genetics, Bacteria, Genetic Complementation Test, lcsh:R, Organisms, Biology and Life Sciences, Proteins, Cell Biology, Flagellar Motility, Gene Expression Regulation, Bacterial, Periplasmic space, MESH: Flagella/physiology, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 030104 developmental biology, MESH: Flagella/ultrastructure, Amniotes, Mutation, lcsh:Q
Abstract

International audience; Pathogenic Leptospira strains are responsible for leptospirosis, a worldwide emerging zoonotic disease. These spirochetes are unique amongst bacteria because of their corkscrew-like cell morphology and their periplasmic flagella. Motility is reported as an important virulence determinant, probably favoring entry and dissemination of pathogenic Leptospira in the host. However, proteins constituting the periplasmic flagella and their role in cell shape, motility and virulence remain poorly described. In this study, we characterized a spontaneous L. interrogans mutant strain lacking motility, correlated with the loss of the characteristic hook-shaped ends, and virulence in the animal model. Whole genome sequencing allowed the identification of one nucleotide deletion in the fliM gene resulting in a premature stop codon, thereby preventing the production of flagellar motor switch protein FliM. Genetic complementation restored cell morphology, motility and virulence comparable to those of wild type cells. Analyses of purified periplasmic flagella revealed a defect in flagella assembly, resulting in shortened flagella compared to the wild type strain. This also correlated with a lower amount of major filament proteins FlaA and FlaB. Altogether, these findings demonstrate that FliM is required for full and correct assembly of the flagella which is essential for motility and virulence.

Published
2016
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8. Bioimage analysis of Shigella infection reveals targeting of colonic crypts

Author

Maryse Moya-Nilges, Giulia Nigro, Martin Sachse, Philippe J. Sansonetti, Ellen T. Arena, Jean-Yves Tinevez, François-Xavier Campbell-Valois, Katharina Nothelfer, Spencer L. Shorte, Benoit S. Marteyn, Pathogénie microbienne moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Dynamique (Plate-Forme) (PFID), Institut Pasteur [Paris] (IP), Microscopie ultrastructurale - Ultrapole (CITECH), Collège de France - Chaire Microbiologie et Maladies infectieuses, Collège de France (CdF (institution)), E.T.A. was a Pasteur Foundation and Pasteur-Roux Fellow. F.-X.C.-V. was a Canadian Institutes of Health Research, European Molecular Biology Organization, Marie-Curie, and Fondation de la Recherche Médicale Fellow. P.J.S. is a Howard Hughes Medical Institute Senior International Research Scholar. This work was supported by the European Research Council (PS Advanced Grants 232798 and 339579), France Bioimaging Infrastructure, supported by the French National Research Agency ANR-10-INSB-04-01 Program Investments for the Future, and the Wellcome Trust., We thank Sèbastien Simard (Welcome Trust, London) for his contributions in OMERO and Pamela Schnupf and Claude Parsot for helpful discussions., European Project: 232798,EC:FP7:ERC,ERC-2008-AdG,HOMEOEPITH(2009), European Project: 339579,EC:FP7:ERC,ERC-2013-ADG,DECRYPT(2014), Tinevez, Jean-Yves, Homeostasis and rupture of the gut epithelium in the presence of commensals and pathogens - HOMEOEPITH - - EC:FP7:ERC2009-02-01 - 2013-07-31 - 232798 - VALID, Decrypting signals in the crypt. - DECRYPT - - EC:FP7:ERC2014-04-01 - 2019-03-31 - 339579 - VALID, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], and Chaire Microbiologie et Maladies infectieuses

Subjects
Fluorescence-lifetime imaging microscopy, Colon, Confocal, [SDV]Life Sciences [q-bio], Crypt, Guinea Pigs, MESH: Intestinal Mucosa / microbiology, MESH: Shigella flexneri / pathogenicity, Biology, medicine.disease_cause, Microbiology, Shigella flexneri, MESH: Guinea Pigs, tissue microbiology, Intestinal mucosa, In vivo, medicine, Animals, Humans, Shigella, MESH: Animals, bioimage analysis, intestinal crypts, Intestinal Mucosa, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Dysentery, Bacillary, Multidisciplinary, MESH: Humans, biology.organism_classification, digestive system diseases, 3. Good health, Cell biology, MESH: Dysentery, Bacillary / pathology, [SDV] Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, PNAS Plus, MESH: Colon / microbiology, Infectious agent, host–pathogen interactions
Abstract

International audience; Few studies within the pathogenic field have used advanced imaging and analytical tools to quantitatively measure pathogenicity in vivo. In this work, we present a novel approach for the investigation of host-pathogen processes based on medium-throughput 3D fluorescence imaging. The guinea pig model for Shigella flexneri invasion of the colonic mucosa was used to monitor the infectious process over time with GFP-expressing S. flexneri. A precise quantitative imaging protocol was devised to follow individual S. flexneri in a large tissue volume. An extensive dataset of confocal images was obtained and processed to extract specific quantitative information regarding the progression of S. flexneri infection in an unbiased and exhaustive manner. Specific parameters included the analysis of S. flexneri positions relative to the epithelial surface, S. flexneri density within the tissue, and volume of tissue destruction. In particular, at early time points, there was a clear association of S. flexneri with crypts, key morphological features of the colonic mucosa. Numerical simulations based on random bacterial entry confirmed the bias of experimentally measured S. flexneri for early crypt targeting. The application of a correlative light and electron microscopy technique adapted for thick tissue samples further confirmed the location of S. flexneri within colonocytes at the mouth of crypts. This quantitative imaging approach is a novel means to examine host-pathogen systems in a tailored and robust manner, inclusive of the infectious agent.

Published
2015
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9. Crystal structure of glycoprotein C from a hantavirus virus in the post-fusion conformation

Author

Gérard Pehau-Arnaudet, Pablo Guardado-Calvo, Félix A. Rey, M. Alejandra Tortorici, Jean Luc Jestin, Scott A. Jeffers, Patrick England, Nicole D. Tischler, Eva Stettner, Jimena Pérez-Vargas, Eduardo A Bignon, Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Molecular Virology Laboratory, Fundación Ciencia & Vida, Microscopie ultrastructurale - Ultrapole (CITECH), Institut Pasteur [Paris] (IP), Biophysique des macromolécules et leurs interactions, FAR and PGC acknowledge support the Infect-ERA IMI European network, program 'HantaHunt' and its coordinator, Professor Andreas Herrmann. FAR also received funding from the 'Integrative Biology of Emerging Infectious Diseases' Labex (Laboratoire d'Excellence ) grant N° ANR-10-LABX-62-IBEID (French Government's 'Investissements d'Avenir' program). ES was funded as 'Experienced Researche' (ER) by the Marie Curie Training Network 'Virus Entry' (Call:FP7-PEOPLE-2007-1-1-ITN. NDT received support from FONDECYT 1140050 and Basal PFB-16 grants from CONICYT (Chile). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 235649,EC:FP7:PEOPLE,FP7-PEOPLE-ITN-2008,VIRUS ENTRY(2009), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]

Subjects
RNA viruses, Retinal Ganglion Cells, 0301 basic medicine, Orthohantavirus, Orthobunyavirus, Protein Conformation, viruses, Cell Membranes, Andes virus, Pathology and Laboratory Medicine, medicine.disease_cause, Membrane Fusion, Physical Chemistry, Viral Envelope Proteins, Animal Cells, Bunyaviruses, Medicine and Health Sciences, Biology (General), Neurons, Crystallography, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Physics, virus diseases, Condensed Matter Physics, 3. Good health, Chemistry, Medical Microbiology, Viral Pathogens, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Viruses, Physical Sciences, Crystal Structure, Mathematisch-Naturwissenschaftliche Fakultät, Pathogens, Cellular Structures and Organelles, Cellular Types, Research Article, Hantavirus, Ganglion Cells, QH301-705.5, Viral protein, 030106 microbiology, Immunology, Viral Structure, Biology, Microbiology, Structure-Activity Relationship, 03 medical and health sciences, Viral entry, Virology, Genetics, medicine, Solid State Physics, Animals, Humans, ddc:610, Vesicles, Microbial Pathogens, Molecular Biology, Institut für Biochemie und Biologie, Hantaan virus, Glycoproteins, Hantavirus pulmonary syndrome, Biology and life sciences, Chemical Bonding, Organisms, Afferent Neurons, Lipid bilayer fusion, Hydrogen Bonding, Cell Biology, RC581-607, Surface Plasmon Resonance, Fusion protein, 030104 developmental biology, Cellular Neuroscience, Liposomes, Bunyavirus, Parasitology, Immunologic diseases. Allergy, viral fusion, Neuroscience
Abstract

Hantaviruses are zoonotic viruses transmitted to humans by persistently infected rodents, giving rise to serious outbreaks of hemorrhagic fever with renal syndrome (HFRS) or of hantavirus pulmonary syndrome (HPS), depending on the virus, which are associated with high case fatality rates. There is only limited knowledge about the organization of the viral particles and in particular, about the hantavirus membrane fusion glycoprotein Gc, the function of which is essential for virus entry. We describe here the X-ray structures of Gc from Hantaan virus, the type species hantavirus and responsible for HFRS, both in its neutral pH, monomeric pre-fusion conformation, and in its acidic pH, trimeric post-fusion form. The structures confirm the prediction that Gc is a class II fusion protein, containing the characteristic β-sheet rich domains termed I, II and III as initially identified in the fusion proteins of arboviruses such as alpha- and flaviviruses. The structures also show a number of features of Gc that are distinct from arbovirus class II proteins. In particular, hantavirus Gc inserts residues from three different loops into the target membrane to drive fusion, as confirmed functionally by structure-guided mutagenesis on the HPS-inducing Andes virus, instead of having a single “fusion loop”. We further show that the membrane interacting region of Gc becomes structured only at acidic pH via a set of polar and electrostatic interactions. Furthermore, the structure reveals that hantavirus Gc has an additional N-terminal “tail” that is crucial in stabilizing the post-fusion trimer, accompanying the swapping of domain III in the quaternary arrangement of the trimer as compared to the standard class II fusion proteins. The mechanistic understandings derived from these data are likely to provide a unique handle for devising treatments against these human pathogens., Author Summary Hantaviruses belong to the Bunyaviridae family of enveloped viruses. This family englobes in total five established genera: Tospovirus (infecting plants), and Phlebovirus, Orthobunyavirus, Nairovirus and Hantavirus infecting animals, some of which cause serious disease in humans. An important characteristic of the hantaviruses is that they are not transmitted to humans by arthropod vectors, as those from the other genera, but by direct exposure to excretions from infected small mammals. As all enveloped viruses, they require the activity of a membrane fusogenic protein, Gc, for entry into their target cells. Our structural analysis of the hantavirus fusion protein Gc led to the identification of a conserved pattern of cysteines involved in disulfide bonds stabilizing the Gc fold. This motif is matched exclusively by all of the available bunyavirus Gc sequences in the database, with the notable exception of phlebovirus Gc, which appears closer in structure to the fusion proteins of other families of arthropod-borne viruses, such as the flaviviruses and alphaviruses. This analysis further suggests mechanistic similarities with hantaviruses in the fusion mechanism of viruses in the remaining three most closely related bunyavirus genera, which we propose belong to a new separate sub-class of fusion proteins with a multipartite membrane targeting region.

Published
2016
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10. Emergence and Transmission of Arbovirus Evolutionary Intermediates with Epidemic Potential

Author

Kenneth A. Stapleford, Sreyrath Lay, Veasna Duong, Isabelle Bonne, Camilo Arias-Goeta, Christine Schmitt, Hervé Blanc, Anna-Bella Failloux, Stéphanie Beaucourt, Kathryn Rozen-Gagnon, Lark L. Coffey, Turkan Haliloglu, Ofer Isakov, Noam Shomron, Marco Vignuzzi, Antonio V. Bordería, Philippe Buchy, Nir Ben-Tal, Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of California [Davis] (UC Davis), University of California (UC), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Sackler Faculty of Medicine, Tel Aviv University (TAU), Arbovirus et Insectes Vecteurs - Arboviruses and Insect Vectors, Institut Pasteur [Paris] (IP), Boǧaziçi üniversitesi = Boğaziçi University [Istanbul], Microscopie ultrastructurale - Ultrapole (CITECH), This work was supported by the European Research Council (ERC Starting Grant No. 242719), by the Bill and Melinda Gates Foundation Grand Challenges Exploration Initiative, the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant ANR-10-LABX-62-IBEID), and the Israel-France High Council for Science and Technology Research 'Complexity in Biology' program. Salary for L.L.C. and K.A.S. was provided by the Region of Ile-de-France DIM program on Infectious, Parasitic or Nosocomial Emerging Diseases and the Philippe Foundation. Salary for A.V.B. was supported by the French National grant ANR-09-JCJC-0118-1. Salary for C.A.-G. was supported by the French Ministry of Superior Education and Research. N.B.-T. and T.H. were supported by NATO traveling grant CBP.MD.CLG 984340., We are grateful to Ngan Chantha, Huy Rekol, and the team of the National Malaria Centre in Cambodia for providing clinical specimens. We thank Christophe Paupy (IRD), Louis Lambrechts, and Paul Reiter (IP) for providing some mosquito strains., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-09-JCJC-0118,QuasispeciesVax(2009), European Project: 242719,EC:FP7:ERC,ERC-2009-StG,RNAVIRUSPOPDIVNVAX(2009), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of California, Tel Aviv University [Tel Aviv], Institut Pasteur [Paris], and Boğaziçi University [Istanbul]

Subjects
Cancer Research, Mutation rate, viruses, MESH: Chikungunya Fever, medicine.disease_cause, Virus Replication, Aedes, MESH: Arboviruses, MESH: Animals, MESH: Genetic Variation, Chikungunya, Epidemic strain, Genetics, Mammals, Transmission (medicine), virus diseases, MESH: Aedes, Viral Load, Biological Evolution, 3. Good health, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Host-Pathogen Interactions, MESH: Arbovirus Infections, Female, MESH: Viral Load, Cambodia, Chikungunya virus, MESH: Biological Evolution, MESH: Insect Vectors, Biology, Arbovirus Infections, Microbiology, Arbovirus, MESH: Mammals, Virus, Article, MESH: Mice, Inbred C57BL, Immunology and Microbiology(all), Virology, parasitic diseases, medicine, Animals, Humans, MESH: Saliva, Epidemics, Saliva, Molecular Biology, MESH: Epidemics, MESH: Humans, MESH: Cambodia, MESH: Host-Pathogen Interactions, MESH: Virus Replication, fungi, RNA, Genetic Variation, MESH: Chikungunya virus, medicine.disease, Insect Vectors, Mice, Inbred C57BL, Disease Models, Animal, Population bottleneck, Culicidae, Chikungunya Fever, Parasitology, MESH: Disease Models, Animal, MESH: Culicidae, MESH: Female, Arboviruses
Abstract

Comment in: "Toward an activist agenda for monitoring virus emergence."https://doi.org/10.1016/j.chom.2014.05.014; International audience; The high replication and mutation rates of RNA viruses can result in the emergence of new epidemic variants. Thus, the ability to follow host-specific evolutionary trajectories of viruses is essential to predict and prevent epidemics. By studying the spatial and temporal evolution of chikungunya virus during natural transmission between mosquitoes and mammals, we have identified viral evolutionary intermediates prior to emergence. Analysis of virus populations at anatomical barriers revealed that the mosquito midgut and salivary gland pose population bottlenecks. By focusing on virus subpopulations in the saliva of multiple mosquito strains, we recapit-ulated the emergence of a recent epidemic strain of chikungunya and identified E1 glycoprotein mutations with potential to emerge in the future. These mutations confer fitness advantages in mosquito and mammalian hosts by altering virion stability and fusogenic activity. Thus, virus evolutionary tra-jectories can be predicted and studied in the short term before new variants displace currently circulating strains.

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