<br>RIG-I 样受体激活驱动 I 型 IFN 和抗病毒信号传导，限制汉坦正汉坦病毒复制。,PLoS Pathogens

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RIG-I 样受体激活驱动 I 型 IFN 和抗病毒信号传导，限制汉坦正汉坦病毒复制。
PLoS Pathogens ( IF 5.5 ) Pub Date : 2020-04-24 , DOI: 10.1371/journal.ppat.1008483
Alison M Kell ₁ , Emily A Hemann ₂ , J Bryan Turnbull ₂ , Michael Gale _{2,

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Affiliation

致病性汉坦病毒（正汉坦病毒科）存在于啮齿动物宿主中，通过吸入啮齿动物排泄物而传播给人类。人类汉坦病毒病的特征是局部血管渗漏和循环促炎细胞因子水平升高。尽管致命的人畜共患病毒向人类传播的可能性持续存在，但导致先天免疫激活的汉坦病毒的特定病毒与宿主相互作用，以及这些过程如何传播疾病，仍不清楚。在这项研究中，我们研究了汉坦正汉坦病毒（HTNV）感染的病毒识别和先天免疫激活机制。我们确定 RIG-I 样受体 (RLR) 途径对于先天免疫激活、干扰素 (IFN) 产生和响应人类内皮细胞和代表小鼠细胞中 HTNV 感染的干扰素刺激基因 (ISG) 表达至关重要。非水库宿主。我们的结果表明，先天免疫激活和通过 RLR 途径的信号传导取决于病毒复制，其中宿主反应可以以依赖于 1 型干扰素受体 (IFNAR) 的方式显着限制靶细胞中的复制。重要的是，在非储存宿主鼠模型感染 HTNV 后，与野生型动物相比，IFNAR 缺陷型小鼠的病毒载量更高，持久性更强，并且病毒向肺、脾和肾的传播更大。令人惊讶的是，这种反应在体内与 MAVS 无关。这些组织中的先天免疫分析表明，HTNV 感染在感染早期会触发 IFN 调节的细胞因子的表达。我们得出的结论是，RLR 途径对于识别 HTNV 感染以指导先天免疫激活和体外病毒复制控制至关重要，并且 IFN 和细胞因子调节的其他病毒感应和先天免疫反应途径有助于体内 HTNV 的控制。这些结果揭示了先天免疫调节在驱动 HTNV 感染不同结果中的关键作用，并为研究确定缓解人类汉坦病毒病的治疗靶点提供信息。

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RIG-I-like receptor activation drives type I IFN and antiviral signaling to limit Hantaan orthohantavirus replication.

Pathogenic hantaviruses, genus Orthohantaviridae, are maintained in rodent reservoirs with zoonotic transmission to humans occurring through inhalation of rodent excreta. Hantavirus disease in humans is characterized by localized vascular leakage and elevated levels of circulating proinflammatory cytokines. Despite the constant potential for deadly zoonotic transmission to humans, specific virus-host interactions of hantaviruses that lead to innate immune activation, and how these processes impart disease, remain unclear. In this study, we examined the mechanisms of viral recognition and innate immune activation of Hantaan orthohantavirus (HTNV) infection. We identified the RIG-I-like receptor (RLR) pathway as essential for innate immune activation, interferon (IFN) production, and interferon stimulated gene (ISG) expression in response to HTNV infection in human endothelial cells, and in murine cells representative of a non-reservoir host. Our results demonstrate that innate immune activation and signaling through the RLR pathway depends on viral replication wherein the host response can significantly restrict replication in target cells in a manner dependent on the type 1 interferon receptor (IFNAR). Importantly, following HTNV infection of a non-reservoir host murine model, IFNAR-deficient mice had higher viral loads, increased persistence, and greater viral dissemination to lung, spleen, and kidney compared to wild-type animals. Surprisingly, this response was MAVS independent in vivo. Innate immune profiling in these tissues demonstrates that HTNV infection triggers expression of IFN-regulated cytokines early during infection. We conclude that the RLR pathway is essential for recognition of HTNV infection to direct innate immune activation and control of viral replication in vitro, and that additional virus sensing and innate immune response pathways of IFN and cytokine regulation contribute to control of HTNV in vivo. These results reveal a critical role for innate immune regulation in driving divergent outcomes of HTNV infection, and serve to inform studies to identify therapeutic targets to alleviate human hantavirus disease.

更新日期：2020-04-24

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