Gut Microbiota Modulation of Chikungunya Virus Infection and Pathogenesis

项目概要 基孔肯雅病毒 (CHIKV) 是一种通过蚊子传播的、有正链包膜的甲病毒，可导致全球性疾病 人类疾病。目前，尚无用于治疗或预防的抗病毒药物或许可的疫苗 任何甲病毒感染。虽然年龄、免疫状态和先前存在的慢性疾病与 严重 CHIKV 感染的风险增加，但获得性因素在疾病进展中的作用尚不清楚。 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 指导先天免疫细胞反应来控制循环中单核细胞和单核细胞的 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 会广泛传播，感染后就会出现关节炎。 免疫细胞浸润关节。该提案结合了具有甲病毒发病机制专业知识的研究人员 免疫（Diamond）以及疾病中肠道微生物群的研究（Handley、Stappenbeck 和 Fischbach）。 使用一套转基因小鼠和微生物组重建实验，并结合详细的病毒学和 免疫学分析中，我们将解决以下关键问题：（a）哪些免疫细胞协调 CHIKV 感染后快速的全身性 IFN 反应（例如 pDC）（b）哪些免疫信号限制病毒感染 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 的产生以及 循环免疫细胞的贩运？ (d) 微生物群的哪些成分（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，我们期望将 具有调节先天抗病毒反应的特定共生细菌的微生物衍生成分 甲病毒感染、传播、关节疾病和可能的传播。除了增强我们的 了解甲病毒发病机制的后天决定因素，该提案的研究结果可以提供信息 更广泛地说，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 以及其他病毒的发病机制。

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.