Gut Microbiota Modulation of Chikungunya Virus Infection and Pathogenesis

项目总结 基孔肯雅病毒(CHIKV)是一种蚊子传播的正链包膜甲型病毒，可引起全球 人类的疾病。目前，尚无抗病毒药物或获得许可的疫苗用于治疗或预防 有没有甲型病毒感染。而年龄、免疫状况和既往慢性病与 随着严重CHIKV感染风险的增加，获得性因素在疾病进展中的作用还知之甚少。 我们的初步数据表明，微生物区系调节CHIKV的感染、传播和肌肉骨骼 炎症和疾病通过肠道细菌和胆汁酸发出的信号之前未确定的轴 引导先天免疫细胞反应控制CHIKV感染循环单核细胞及单核细胞 转移到受影响的关节组织。我们假设特定的肠道细菌和它们的微生物成分 通过调节pDC和pDC的抗I型干扰素和炎症反应来调节CHIKV的致病作用 单核细胞。在缺乏这些微生物信号的情况下，CHIKV广泛传播，继而发生关节炎 免疫细胞联合侵袭。这项建议将研究人员与甲型病毒致病机理的专业知识结合在一起。 和免疫学(戴蒙德)和疾病中肠道微生物区系的研究(汉德利、斯塔彭贝克和费施巴赫)。 利用一组转基因小鼠和微生物组重建实验，结合详细的病毒学和 在免疫学分析中，我们将解决以下关键问题：(A)哪些免疫细胞协调 CHIKV感染后的快速全身干扰素反应(例如，pDC)(B)哪些免疫线索限制病毒感染 循环免疫细胞(如单核细胞)？(C)肠道微生物区系如何调节PDC干扰素的产生和 循环免疫细胞的贩运？以及(D)微生物区系的哪些成分(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，我们希望将 特定共生细菌的微生物衍生成分，具有天然的抗病毒反应，调节 甲型病毒感染、传播、关节疾病，以及可能的传播。除了增强我们的 对甲型病毒致病的获得性决定因素的理解，这一建议的发现可能会为 更广泛地说，我们对肠道微生物区系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.