Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors.
Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors.
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DOI：
10.1016/j.chom.2013.07.005
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发表时间：
2013-08-14
影响因子：
30.3
通讯作者：
Young JA
中科院分区：
文献类型：
--
作者：
Bhattacharyya S;Zagórska A;Lew ED;Shrestha B;Rothlin CV;Naughton J;Diamond MS;Lemke G;Young JA
当被配体Gas6和蛋白S激活后，受体酪氨酸激酶促进吞噬细胞对凋亡细胞的清除，并下调由Toll样受体和I型干扰素(IFN)启动的免疫反应。许多被包裹的病毒在其膜上显示磷脂磷脂酰丝氨酸，通过它与Gas6和S蛋白结合，并与受体结合。我们发现，配体包裹的病毒激活树突状细胞(DC)上的受体，抑制I型干扰素信号，从而逃避宿主免疫，促进感染。在病毒攻击时，缺乏的DC表现出与野生型细胞相比升高的I型干扰素应答。因此，缺失的DC对黄病毒和伪型逆转录病毒的感染具有相对的抵抗力，但感染可以通过I型干扰素中和抗体恢复。相应地，一种激酶抑制剂可以拮抗野生型DC的感染。因此，受体被病毒激活，以减弱I型干扰素信号，并代表潜在的治疗靶点。
Upon activation by the ligands Gas6 and Protein S, TAM receptor tyrosine kinases promote phagocytic clearance of apoptotic cells and downregulate immune responses initiated by Toll-like receptors and type I interferons (IFNs). Many enveloped viruses display the phospholipid phosphatidylserine on their membranes, through which they bind Gas6 and Protein S and engage TAM receptors. We find that ligand-coated viruses activate TAM receptors on dendritic cells (DCs), dampen type I IFN signaling, and thereby evade host immunity and promote infection. Upon virus challenge, TAM-deficient DCs display type I IFN responses that are elevated in comparison to wild-type cells. As a consequence, TAM-deficient DCs are relatively resistant to infection by flaviviruses and pseudotyped retroviruses, but infection can be restored with neutralizing type I IFN antibodies. Correspondingly, a TAM kinase inhibitor antagonizes the infection of wild-type DCs. Thus, TAM receptors are engaged by viruses in order to attenuate type I IFN signaling and represent potential therapeutic targets.
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