The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity.
The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity.
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DOI：
10.1038/nm.3974
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发表时间：
2015-12
期刊：
影响因子：
82.9
通讯作者：
Diamond MS
中科院分区：
文献类型：
--
作者：
Miner JJ;Daniels BP;Shrestha B;Proenca-Modena JL;Lew ED;Lazear HM;Gorman MJ;Lemke G;Klein RS;Diamond MS
TAM受体Tyro 3、Axl和Mertk是受体酪氨酸激酶，其在与其配体Gas 6和蛋白S接合后抑制宿主先天性免疫应答，所述配体Gas 6和蛋白S识别凋亡细胞上的磷脂酰丝氨酸。在一种凋亡模拟形式中，许多包膜病毒在其膜的外小叶上显示磷脂酰丝氨酸，使得TAM受体活化和抗病毒应答下调。因此，我们假设TAM受体的缺乏会增强抗病毒反应并防止病毒感染。出乎意料的是，缺乏Mertk和/或Axl但不缺乏Tyro 3的小鼠表现出对神经侵入性西尼罗河病毒和拉克罗斯病毒感染的更大脆弱性。这种表型与血脑屏障通透性增加有关，这增强了病毒进入大脑并感染大脑。Mertk的激活与IFN-β协同作用以收紧细胞连接并阻止病毒穿过脑微血管内皮细胞。由于TAM受体限制了神经侵袭性病毒的发病机制，这些发现对目前正在临床开发的TAM拮抗剂具有意义。
The TAM receptors Tyro3, Axl, and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands, Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and down-regulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl but not Tyro3 exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with IFN-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.