Axl mediates ZIKA virus entry in human glial cells and modulates innate immune responses

Laurent Meertens; Athena Labeau; Ophélie Dejarnac; Sara Cipriani; Laura Sinigaglia; Lucie Bonnet-Madin; Tifenn Le Charpentier; Mohamed Hafirassou; Alessia Zamborlini; Van-Mai Cao-Lormeau; Muriel Coulpier; Dorothée Missé; Nolwenn Jouvenet; Ray Tabibiazar; Pierre Gressens; Olivier Schwartz; Ali Amara

doi:10.1016/j.celrep.2016.12.045

Article dans une revue

Axl mediates ZIKA virus entry in human glial cells and modulates innate immune responses

Laurent Meertens ^{1, 2} Athena Labeau ^{1, 2} Ophélie Dejarnac ^{1, 2} Sara Cipriani ³ Laura Sinigaglia ⁴ Lucie Bonnet-Madin ^{1, 2} Tifenn Le Charpentier ³ Mohamed Hafirassou ^{1, 2} Alessia Zamborlini ^{1, 2, 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 ^{1, 2}

1 PVM (UMR_7151) - Pathologie et virologie moléculaire

2 Institut Universitaire d'Hématologie [Hôpital Saint-Louis - APHP]

3 PROTECT - Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies

4 Génomique virale et vaccination

5 CNAM - Conservatoire National des Arts et Métiers [CNAM]

6 Emerging Infectious Diseases

7 VIRO - Virologie UMR1161

8 MIVEGEC - Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle

9 Ruga Corporation

10 Virus et Immunité

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.

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Article dans une revue

Domaine :

Sciences du Vivant [q-bio] / Immunologie / Immunité innée

Sciences du Vivant [q-bio] / Microbiologie et Parasitologie / Virologie

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