Gut Microbiota Modulation of Chikungunya Virus Infection and Pathogenesis

项目摘要 基孔肯雅病毒（CHIKV）是一种蚊子传播的正链包膜甲病毒，可引起全球性 人类的疾病。目前，没有抗病毒剂或许可的疫苗存在用于治疗或预防 任何甲病毒感染虽然年龄，免疫状态和预先存在的慢性疾病与 由于严重CHIKV感染的风险增加，获得性因素在疾病进展中的作用知之甚少。 我们的初步数据表明，微生物群调节CHIKV感染，传播和肌肉骨骼 炎症和疾病通过以前未定义的轴，通过该轴来自肠道细菌和胆汁酸的信号 指导先天免疫细胞应答以控制循环中单核细胞和单核细胞中CHIKV感染 迁移至受影响的关节组织。我们假设特定的肠道细菌及其微生物成分 通过调节pDC中的抗病毒I型IFN和炎症反应来调节CHIKV发病机制， 单核细胞在缺乏这些微生物信号的情况下，CHIKV广泛传播，并且在感染后关节炎发作。 免疫细胞浸润关节。该提案将研究人员与甲病毒发病机制的专业知识相结合 和免疫（钻石）和疾病中肠道微生物群的研究（汉德利，Stappenbeck和Fischbach）。 使用一套转基因小鼠和微生物组重建实验，结合详细的病毒学和 免疫学分析，我们将解决以下关键问题：（a）哪些免疫细胞协调 CHIKV感染后快速全身性IFN反应（例如，pDC）（B）什么免疫信号限制了 循环免疫细胞（例如，单核细胞）？(c)肠道微生物群如何调节pDC IFN的产生， 循环免疫细胞的运输以及（d）哪些成分（例如，代谢物）调节 抗病毒和炎症反应通过这些详细的机制研究，我们希望将 微生物衍生的成分，具有先天性抗病毒反应，调节 甲病毒感染、传播、关节疾病以及可能的传播。除了增强我们的 了解甲病毒发病机制的获得性决定因素，该提案的发现可以为 更一般地说，我们对肠道微生物群如何塑造先天免疫反应以限制感染的理解 和其他病毒的致病机制。

PROJECT SUMMARY Chikungunya virus (CHIKV) is a mosquito-transmitted, positive-strand enveloped alphavirus that causes global disease in humans. At present, no antiviral agents or licensed vaccines exist for the treatment or prevention of any alphavirus infections. While age, immune status, and pre-existing chronic illness are associated with increased risk of severe CHIKV infection, the role of acquired factors in disease progression is poorly understood. Our preliminary data suggests that the microbiota regulates CHIKV infection, dissemination, and musculoskeletal inflammation and disease through a previously undefined axis by which signals from gut bacteria and bile acids instruct innate immune cell responses to control CHIKV infection of monocytes in circulation and monocyte migration to affected joint tissues. We hypothesize that specific gut bacteria and their microbial constituents modulate CHIKV pathogenesis by regulating antiviral type I IFN and inflammatory responses in pDCs and monocytes. In the absence of these microbial signals, CHIKV disseminates widely, and arthritis ensues after joint infiltration by immune cells. This proposal combines investigators with expertise in alphavirus pathogenesis and immunity (Diamond) and the study of the gut microbiota in disease (Handley, Stappenbeck, and Fischbach). Using a suite of transgenic mice and microbiome reconstitution experiments paired with detailed virological and immunological analyses, we will address the following key questions: (a) which immune cells coordinate the rapid systemic IFN response following CHIKV infection (e.g., pDCs) (b) what immune cues limit viral infection in circulating immune cells (e.g., monocytes)? (c) how does the gut microbiota regulate pDC IFN production and trafficking of circulating immune cells? and (d) which constituents (e.g., metabolites) of the microbiota regulate antiviral and inflammatory responses? Through these detailed mechanistic studies, we expect to link the microbe-derived constituents of specific commensal bacteria with innate antiviral responses that modulate alphavirus infection, dissemination, joint disease, and possibly transmission. Beyond enhancing our understanding of acquired determinants of alphavirus pathogenesis, the findings of this proposal could inform more generally our understanding of how the gut microbiota shapes innate immune responses to limit infection and pathogenesis of other viruses.