Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses

Cell Rep. 2017 Jan 10;18(2):324-333. doi: 10.1016/j.celrep.2016.12.045.

Laurent Meertens ¹, Athena Labeau ², Ophelie Dejarnac ², Sara Cipriani ³, Laura Sinigaglia ⁴, Lucie Bonnet-Madin ², Tifenn Le Charpentier ³, Mohamed Lamine Hafirassou ², Alessia Zamborlini ⁵, Van-Mai Cao-Lormeau ⁶, Muriel Coulpier ⁷, Dorothée Missé ⁸, Nolwenn Jouvenet ⁴, Ray Tabibiazar ⁹, Pierre Gressens ³, Olivier Schwartz ¹⁰, Ali Amara ¹¹

Affiliations

1 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.
2 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.
3 PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, 75019 Paris, France.
4 UMR CNRS 3569, Viral Genomics and Vaccination Unit, Pasteur Institute, 75724 Paris, France.
5 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.
6 Institut Louis Malardé, Papeete, Tahiti, French Polynesia.
7 ANSES, Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UMR Virologie, 94700 Maisons-Alfort, France.
8 Laboratoire MIVEGEC, UMR 224 IRD/CNRS, 34394 Montpellier, France.
9 Ruga Corporation, Two Houston Center, 909 Fannin St., #2000, Houston, TX 77010-1018, USA.
10 Unité Virus et Immunité, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris, France.
11 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.

PMID: 28076778 DOI: 10.1016/j.celrep.2016.12.045

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.