Regulation of Antiviral Responses in Plasmacytoid Dendritic Cells to Chikungunya Virus by the Gut Microbiota

项目摘要 基孔肯雅病毒(CHIKV)是Togaviridae科蚊媒甲型病毒的新成员 这会导致严重的急性和慢性多发性关节炎，并影响全球数百万人。尽管发病率很高 与CHIKV感染和大量处于危险中的人口有关，没有批准的疫苗或疗法是 可用于预防或治疗CHIKV感染。此外，决定症状严重程度的后天因素 或者从急性疾病到慢性疾病的进展情况知之甚少。CHIKV致病的小鼠模型 强调了I型干扰素(IFN)信号在限制病毒传播和防止死亡方面的关键作用 奇卡病毒感染。最近，几项研究表明肠道微生物区系在启动全身干扰素反应中起作用。 或者在远离胃肠道的部位调节病毒的致病机制。尽管有越来越多的证据 肠道微生物区系在肠外部位形成抗病毒反应，它在影响宿主免疫方面的作用 甲型病毒感染尚未得到研究。 拟议的项目建立在大量初步数据的基础上，这些数据表明肠道微生物区系 调节全身固有的抗病毒反应，以限制CHIKV的传播。新城疫病毒皮下感染的研究 无论是口服抗生素(ABX)治疗的小鼠还是无菌(GF)小鼠，都会导致血液和血液中的病毒负荷增加. 远离接种部位的组织。这种增强的病毒传播是由于病毒复制的增加 在血液或脾的单核细胞中。此外，在CHIKV感染后，微生物区系枯竭的小鼠表现出 一种迟钝的系统性I型干扰素反应，通常由循环浆细胞样树突状细胞促进 (PDC)。用未经处理的粪便微生物群转移ABX处理或GF小鼠的重新定植 ABX-NAIVE CONTROLS可恢复I型干扰素反应，并降低血液中的病毒负担。值得注意的是， 引入单一细菌种类(例如，梭状芽孢杆菌)或其衍生的代谢物，次级胆汁酸 将脱氧胆酸(BA)注入ABX治疗或GF小鼠体内也可以限制病毒在血液中的传播。 我推测，特定的BA转化细菌种类指示pDC中的I型干扰素反应。在……里面 如果没有这些微生物因素，pDC就不能足够迅速地产生干扰素并限制 CHIKV感染后循环中的单核细胞，导致病毒传播增强。本提案的目标1 重点是描述肠道微生物群指示PDC功能的免疫途径 奇卡病毒感染。目标2的重点是确定分子成分，特别是bas，由 限制CHIKV感染单核细胞和传播的特定梭状芽胞杆菌物种。加在一起，这些 研究结果将加强我们对肠道微生物区系如何塑造先天免疫反应的理解。 甲型病毒的感染和发病机制，以及可能与单核细胞趋向性的其他病毒。

Project Summary Chikungunya virus (CHIKV) is a re-emerging mosquito-transmitted alphavirus in the Togaviridae family that causes severe acute and chronic polyarthritis and affects millions of people globally. Despite the morbidity associated with CHIKV infection and the large population at risk, no approved vaccines or therapeutics are available to prevent or treat CHIKV infection. Moreover, the acquired factors that dictate the severity of symptoms or progression from acute to chronic disease are poorly understood. Mouse models of CHIKV pathogenesis have highlighted a critical role of type I interferon (IFN) signaling in limiting viral dissemination and preventing fatal CHIKV infection. Recently, several studies have implicated the gut microbiota in priming systemic IFN responses or modulating viral pathogenesis at sites distant from the gastrointestinal tract. Despite the growing evidence that the gut microbiota shapes antiviral responses at extra-intestinal sites, its role in influencing host immunity to alphavirus infections has not been explored. The proposed project builds upon extensive preliminary data suggesting that the gut microbiota modulates systemic innate antiviral responses to limit CHIKV dissemination. Subcutaneous CHIKV infection of either oral antibiotic (Abx)-treated or germ-free (GF) mice results in increased viral burden in the blood and in tissues distant from the inoculation site. This enhanced viral dissemination is due to increased viral replication in monocytes of the blood or spleen. Furthermore, upon CHIKV infection, microbiota-depleted mice demonstrate a blunted systemic type I IFN response that normally is promoted by circulating plasmacytoid dendritic cells (pDCs). Re-colonization of either Abx-treated or GF mice with fecal microbiota transfers derived from untreated Abx-naïve controls restores type I IFN responses and decreases viral burden in the blood. Notably, the introduction of a single bacterial species (e.g., Clostridium) or its derived metabolite, the secondary bile acid (BA), deoxycholic acid, into Abx-treated or GF mice also can restrict viral dissemination in the blood. I hypothesize that specific BA-transforming bacterial species instruct type I IFN responses in pDCs. In the absence of these microbial factors, pDCs cannot respond rapidly enough to produce IFNs and restrict monocytes in circulation from CHIKV infection, leading to enhanced viral dissemination. Aim 1 of this proposal focuses on characterizing immune pathways by which the gut microbiota instructs pDC function in response to CHIKV infection. Aim 2 focuses on identifying the molecular components, specifically BAs, generated by specific Clostridium species that restrict CHIKV infection of monocytes and dissemination. Together, these results will enhance our understanding of how the gut microbiota shapes the innate immune response to limit infection and pathogenesis of alphaviruses, and potentially other viruses with a tropism for monocytes.