Meertens Laurent, Labeau Athena, Dejarnac Ophelie, Cipriani Sara, Sinigaglia Laura, Bonnet-Madin Lucie, Le Charpentier Tifenn, Hafirassou Mohamed Lamine, Zamborlini Alessia, Cao-Lormeau Van-Mai, Coulpier Muriel, Missé Dorothée, Jouvenet Nolwenn, Tabibiazar Ray, Gressens Pierre, Schwartz Olivier, Amara Ali
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.
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.
Cell Rep. 2017 Jan 10;18(2):324-333. doi: 10.1016/j.celrep.2016.12.045.
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.
寨卡病毒（ZIKV）是一种引发神经紊乱和先天性小头畸形的新兴病原体。然而，ZIKV嗜神经性的分子基础仍知之甚少。在此，我们表明Axl在发育中大脑的人类小胶质细胞和星形胶质细胞中表达，并且它介导ZIKV对神经胶质细胞的感染。Axl介导的ZIKV进入需要Axl配体Gas6，Gas6将ZIKV颗粒与神经胶质细胞连接起来。结合后，ZIKV通过网格蛋白介导的内吞作用被内化，并运输到Rab5 + 内体以建立有效感染。在进入过程中，ZIKV / Gas6复合物激活Axl激酶活性，下调干扰素信号传导并促进感染。工程化的Axl诱饵受体MYD1和Axl激酶抑制剂R428可抑制人类神经胶质细胞的ZIKV感染。我们的结果突出了Axl在ZIKV感染神经胶质细胞过程中的双重作用：促进病毒进入和调节先天免疫反应。因此，抑制Axl功能可能是未来抗病毒治疗的潜在靶点。
