title: Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses.
abstract: ZIKA virus (ZIKV) is an emerging pathogen responsible for neurological disorders and congenital microcephaly. However, the molecular basis for ZIKV neurotropism remains poorly understood. Here, we show that Axl is expressed in human microglia and astrocytes in the developing brain and that it mediates ZIKV infection of glial cells. Axl-mediated ZIKV entry requires the Axl ligand Gas6, which bridges ZIKV particles to glial cells. Following binding, ZIKV is internalized through clathrin-mediated endocytosis and traffics to Rab5+ endosomes to establish productive infection. During entry, the ZIKV/Gas6 complex activates Axl kinase activity, which downmodulates interferon signaling and facilitates infection. ZIKV infection of human glial cells is inhibited by MYD1, an engineered Axl decoy receptor, and by the Axl kinase inhibitor R428. Our results highlight the dual role of Axl during ZIKV infection of glial cells: promoting viral entry and modulating innate immune responses. Therefore, inhibiting Axl function may represent a potential target for future antiviral therapies.
authors.affiliation: INSERM U944, CNRS 7212 Laboratoire de Pathologie et Virologie Moléculaire, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France. Electronic address: laurent.meertens@inserm.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meertens
authors.affiliation: INSERM U944, CNRS 7212 Laboratoire de Pathologie et Virologie Moléculaire, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France.
authors.forename: Athena
authors.initials: A
authors.lastname: Labeau
authors.affiliation: INSERM U944, CNRS 7212 Laboratoire de Pathologie et Virologie Moléculaire, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France.
authors.forename: Ophelie
authors.initials: O
authors.lastname: Dejarnac
authors.affiliation: PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, 75019 Paris, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Cipriani
authors.affiliation: UMR CNRS 3569, Viral Genomics and Vaccination Unit, Pasteur Institute, 75724 Paris, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Sinigaglia
authors.affiliation: INSERM U944, CNRS 7212 Laboratoire de Pathologie et Virologie Moléculaire, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Bonnet-Madin
authors.affiliation: PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, 75019 Paris, France.
authors.forename: Tifenn
authors.initials: T
authors.lastname: Le Charpentier
authors.affiliation: INSERM U944, CNRS 7212 Laboratoire de Pathologie et Virologie Moléculaire, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France.
authors.forename: Mohamed Lamine
authors.initials: ML
authors.lastname: Hafirassou
authors.affiliation: INSERM U944, CNRS 7212 Laboratoire de Pathologie et Virologie Moléculaire, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France; Laboratoire PVM, Conservatoire des Arts et Metiers, 292 Rue Saint-Martin, 75003 Paris, France.
authors.forename: Alessia
authors.initials: A
authors.lastname: Zamborlini
authors.affiliation: Institut Louis Malardé, Papeete, Tahiti, French Polynesia.
authors.forename: Van-Mai
authors.initials: VM
authors.lastname: Cao-Lormeau
authors.affiliation: ANSES, Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UMR Virologie, 94700 Maisons-Alfort, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Coulpier
authors.affiliation: Laboratoire MIVEGEC, UMR 224 IRD/CNRS, 34394 Montpellier, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Missé
authors.affiliation: UMR CNRS 3569, Viral Genomics and Vaccination Unit, Pasteur Institute, 75724 Paris, France.
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Jouvenet
authors.affiliation: Ruga Corporation, Two Houston Center, 909 Fannin St., #2000, Houston, TX 77010-1018, USA.
authors.forename: Ray
authors.initials: R
authors.lastname: Tabibiazar
authors.affiliation: PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, 75019 Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: Unité Virus et Immunité, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Schwartz
authors.affiliation: INSERM U944, CNRS 7212 Laboratoire de Pathologie et Virologie Moléculaire, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France. Electronic address: ali.amara@inserm.fr.
authors.forename: Ali
authors.initials: A
authors.lastname: Amara
mesh_terms: D001921:Brain / Q000196:embryology / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D053586:Virus Internalization; D000071244:Zika Virus / Q000502:physiology*; D000071243:Zika Virus Infection / Q000473:pathology / Q000821:virology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D002966:Clathrin; D036341:Intercellular Signaling Peptides and Proteins; D007370:Interferon Type I; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6