Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544.
Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544
Proc Natl Acad Sci U S A. 2018 Jul 3;115(27):E6310-E6318. doi: 10.1073/pnas.1803406115. Epub 2018 Jun 18.
The limited host tropism of numerous viruses causing disease in humans remains incompletely understood. One example is Zika virus (ZIKV), an RNA virus that has reemerged in recent years. Here, we demonstrate that ZIKV efficiently infects fibroblasts from humans, great apes, New and Old World monkeys, but not rodents. ZIKV infection in human-but not murine-cells impairs responses to agonists of the cGMP-AMP synthase/stimulator of IFN genes (cGAS/STING) signaling pathway, suggesting that viral mechanisms to evade antiviral defenses are less effective in rodent cells. Indeed, human, but not mouse, STING is subject to cleavage by proteases encoded by ZIKV, dengue virus, West Nile virus, and Japanese encephalitis virus, but not that of yellow fever virus. The protease cleavage site, located between positions 78/79 of human STING, is only partially conserved in nonhuman primates and rodents, rendering these orthologs resistant to degradation. Genetic disruption of STING increases the susceptibility of mouse-but not human-cells to ZIKV. Accordingly, expression of only mouse, not human, STING in murine STING knockout cells rescues the ZIKV suppression phenotype. STING-deficient mice, however, did not exhibit increased susceptibility, suggesting that other redundant antiviral pathways control ZIKV infection in vivo. Collectively, our data demonstrate that numerous RNA viruses evade cGAS/STING-dependent signaling and affirm the importance of this pathway in shaping the host range of ZIKV. Furthermore, our results explain-at least in part-the decreased permissivity of rodent cells to ZIKV, which could aid in the development of mice model with inheritable susceptibility to ZIKV and other flaviviruses.
许多导致人类疾病的病毒宿主嗜性有限，目前仍不完全清楚。寨卡病毒（ZIKV）就是一个例子，它是一种 RNA 病毒，近年来又重新出现。在这里，我们证明 ZIKV 能有效地感染来自人类、大猿、新旧世界猴的成纤维细胞，但不能感染啮齿动物。ZIKV 在人类细胞而非鼠类细胞中的感染会损害对 cGMP-AMP 合酶/干扰素基因刺激物（cGAS/STING）信号通路激动剂的反应，这表明病毒逃避抗病毒防御的机制在鼠类细胞中效果较差。事实上，人类 STING 而不是鼠类 STING 可被 ZIKV、登革热病毒、西尼罗河病毒和日本脑炎病毒编码的蛋白酶切割，而黄热病毒则不能。蛋白酶切割位点位于人类 STING 的 78/79 位氨基酸之间，在非人类灵长类动物和啮齿动物中只有部分保守，使这些同源物不易降解。STING 的基因缺失会增加鼠类细胞而非人类细胞对 ZIKV 的易感性。因此，只有鼠类而非人类的 STING 在鼠类 STING 敲除细胞中的表达才能挽救 ZIKV 的抑制表型。然而，STING 缺陷型小鼠并没有表现出更高的易感性，这表明其他冗余的抗病毒途径在体内控制 ZIKV 感染。总之，我们的数据表明，许多 RNA 病毒逃避了 cGAS/STING 依赖性信号转导，并证实了该途径在塑造 ZIKV 宿主范围中的重要性。此外，我们的结果至少部分解释了鼠类细胞对 ZIKV 的低易感性，这有助于开发对 ZIKV 和其他黄病毒具有遗传易感性的小鼠模型。
