A Critical Role for STING Signaling in Limiting Pathogenesis of Chikungunya Virus
A Critical Role for STING Signaling in Limiting Pathogenesis of Chikungunya Virus
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DOI：
10.1093/infdis/jiaa694
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发表时间：
2021-06-15
影响因子：
6.4
通讯作者：
Wang, Penghua
中科院分区：
文献类型：
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作者：
Geng, Tingting;Lin, Tao;Wang, Penghua
干扰素基因刺激因子（STING）途径控制DNA和RNA病毒感染。STING对于DNA病毒感染期间诱导先天免疫应答是必不可少的，而其针对RNA病毒的机制在很大程度上仍不清楚。我们发现STING信号对于限制基孔肯雅病毒感染和关节炎发病机制至关重要。刺缺陷小鼠（刺（gt/gt））在整个病毒血症阶段和病毒负荷在脚一过性升高的病毒血症，与正常的I型IFN反应。与野生型小鼠相比，蜇伤（gt/gt）小鼠表现出更大的足部肿胀、关节损伤和免疫细胞浸润。有趣的是，在Sting（gt/gt）小鼠中，干扰素-γ和Cxcl 10的表达持续上调约7至10倍，并与关节炎进展同步进一步升高。然而，中性粒细胞的趋化因子和激活因子Cxcl 5、Cxcl 7和Cxcr 2的表达在Sting（gt/gt）关节中受到抑制。这些结果表明，STING缺乏导致异常的趋化因子反应，促进CHIKV关节炎的发病机制。使用小鼠模型，我们发现Sting缺乏导致基孔肯雅病毒感染增加，足垫和关节炎症，以及干扰素-γ和Cxcl 10在关节中的表达。
The stimulator of interferon gene (STING) pathway controls both DNA and RNA virus infection. STING is essential for induction of innate immune responses during DNA virus infection, while its mechanism against RNA virus remains largely elusive. We show that STING signaling is crucial for restricting chikungunya virus infection and arthritis pathogenesis. Sting-deficient mice (Sting(gt/gt)) had elevated viremia throughout the viremic stage and viral burden in feet transiently, with a normal type I IFN response. Sting(gt/gt) mice presented much greater foot swelling, joint damage, and immune cell infiltration than wild-type mice. Intriguingly, expression of interferon-gamma and Cxcl10 was continuously upregulated by approximately 7 to 10-fold and further elevated in Sting(gt/gt) mice synchronously with arthritis progression. However, expression of chemoattractants for and activators of neutrophils, Cxcl5, Cxcl7, and Cxcr2 was suppressed in Sting(gt/gt) joints. These results demonstrate that STING deficiency leads to an aberrant chemokine response that promotes pathogenesis of CHIKV arthritis.Using a mouse model, we found that Sting deficiency resulted in increased chikungunya virus infection, inflammation in the footpad and joint, as well as interferon-gamma and Cxcl10 expression in the joint.