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

Laurent Meertens; Athena Labeau; Ophelie Dejarnac; Sara Cipriani; Laura Sinigaglia; Lucie Bonnet-Madin; Tifenn Le Charpentier; Mohamed Lamine 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

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

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

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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.

Original language	English
Pages (from-to)	324-333
Number of pages	10
Journal	Cell Reports
Volume	18
Issue number	2
Early online date	10 Jan 2017
DOIs	https://doi.org/10.1016/j.celrep.2016.12.045
Publication status	Published - 10 Jan 2017

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Axl Mediates Zika Virus Entry in Human Glial Cells_MEERTENS_Published10January2017_GOLD VoR (CC-BY-NC-ND)Final published version, 2.53 MBLicence: CC BY-NC-ND

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Meertens, L., Labeau, A., Dejarnac, O., Cipriani, S., Sinigaglia, L., Bonnet-Madin, L., Le Charpentier, T., Hafirassou, M. L., Zamborlini, A., Cao-Lormeau, V.-M., Coulpier, M., Missé, D., Jouvenet, N., Tabibiazar, R., Gressens, P., Schwartz, O., & Amara, A. (2017). Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses. Cell Reports, 18(2), 324-333. https://doi.org/10.1016/j.celrep.2016.12.045

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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.",

author = "Laurent Meertens and Athena Labeau and Ophelie Dejarnac and Sara Cipriani and Laura Sinigaglia and Lucie Bonnet-Madin and {Le Charpentier}, Tifenn and Hafirassou, {Mohamed Lamine} and Alessia Zamborlini and Van-Mai Cao-Lormeau and Muriel Coulpier and Doroth{\'e}e Miss{\'e} and Nolwenn Jouvenet and Ray Tabibiazar and Pierre Gressens and Olivier Schwartz and Ali Amara",

year = "2017",

month = jan,

day = "10",

doi = "10.1016/j.celrep.2016.12.045",

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Meertens, L, Labeau, A, Dejarnac, O, Cipriani, S, Sinigaglia, L, Bonnet-Madin, L, Le Charpentier, T, Hafirassou, ML, Zamborlini, A, Cao-Lormeau, V-M, Coulpier, M, Missé, D, Jouvenet, N, Tabibiazar, R, Gressens, P, Schwartz, O & Amara, A 2017, 'Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses', Cell Reports, vol. 18, no. 2, pp. 324-333. https://doi.org/10.1016/j.celrep.2016.12.045

TY - JOUR

T1 - Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses

AU - Meertens, Laurent

AU - Labeau, Athena

AU - Dejarnac, Ophelie

AU - Cipriani, Sara

AU - Sinigaglia, Laura

AU - Bonnet-Madin, Lucie

AU - Le Charpentier, Tifenn

AU - Hafirassou, Mohamed Lamine

AU - Zamborlini, Alessia

AU - Cao-Lormeau, Van-Mai

AU - Coulpier, Muriel

AU - Missé, Dorothée

AU - Jouvenet, Nolwenn

AU - Tabibiazar, Ray

AU - Gressens, Pierre

AU - Schwartz, Olivier

AU - Amara, Ali

PY - 2017/1/10

Y1 - 2017/1/10

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2016.12.045

DO - 10.1016/j.celrep.2016.12.045

M3 - Article

C2 - 28076778

SN - 2211-1247

VL - 18

SP - 324

EP - 333

JO - Cell Reports

JF - Cell Reports

IS - 2

ER -

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

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