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

肠道微生物群调节浆细胞样树突状细胞对基孔肯雅病毒的抗病毒反应

基本信息

批准号：
10328491
负责人：
Emma Suening Winkler
金额：
$ 5.18万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328491
关键词：
Acute Affect Alphavirus Alphavirus Infections Antibiotics Antibodies Antiviral Response Bile Acids Blood Blood Circulation Bone Marrow Cell physiology Chikungunya virus Chimera organism Chromatin Chronic Chronic Disease Clostridium Culicidae Data Dendritic Cells Deoxycholic Acid Distant Epigenetic Process Event Family Gastrointestinal tract structure Genes Genetic Genetic Transcription Germ-Free Immune Immune response Immunity Immunologics Infection Innate Immune Response Interferon Type I Interferons Intestines Knockout Mice Mediating Molecular Morbidity - disease rate Mus Oral Pathogenesis Pathway interactions Persons Polyarthritides Populations at Risk RNA Regulation Research Role Scheme Severities Shapes Signal Transduction Site Spleen Symptoms TLR7 gene Therapeutic Tissues Togaviridae Tropism Vaccines Viral Viral Load result Viral Pathogenesis Virus Virus Replication XCL1 gene acquired factor bile acid metabolism cell type chikungunya infection experimental study fecal microbiota genetic approach gut bacteria gut microbiota microbial microbiota monocyte mouse model mutant prevent reconstitution response subcutaneous

项目摘要

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.

项目摘要 Chikungunya病毒（Chikv）是在Togaviridae家族中重新出现的蚊子变速器这会导致严重的急性和慢性多性关节炎，并影响全球数百万人。尽管发病率与CHIKV感染和处于危险中的大量人群相关，没有批准的疫苗或治疗是可用于预防或治疗CHIKV感染。此外，决定症状严重程度的获得因素或从急性到慢性疾病的进展知之甚少。 chikv发病机理的小鼠模型强调了I型干扰素（IFN）信号传导在限制病毒传播和防止致命的关键作用 CHIKV感染。最近，一些研究在启动全身IFN反应中实施了肠道菌群或调节远离胃肠道的部位的病毒发病机理。尽管有越来越多的证据肠道菌群在肠外部位形成抗病毒反应，其在影响宿主免疫中的作用尚未探索α病毒感染。拟议的项目建立在广泛的初步数据的基础上，表明肠道菌群调节系统性的先天抗病毒反应以限制Chikv传播。皮下CHIKV感染口服抗生素（ABX）治疗或无菌（GF）小鼠会导致血液中的病毒灼伤增加组织与接种部位的分类。这种增强的病毒传播是由于病毒复制增加引起的在血液或sleen的单核细胞中。此外，在Chikv感染后，贫血小鼠证明了通常通过循环的塑形树突状细胞促进的钝的全身I型IFN响应（PDC）。用未经处理的粪便菌群转移对ABX处理的或GF小鼠的重新殖民化 ABX-NOïve控制可恢复I型IFN反应，并减少血液中的病毒燃烧。值得注意的是引入单一细菌（例如梭状芽胞杆菌）或其衍生代谢产物，即二胆酸（BA），脱氧胆酸进入ABX处理或GF小鼠也可以限制血液中的病毒传播。我假设特定的BA转化细菌指示PDC中的I型IFN反应。在缺乏这些微生物因素，PDC不能迅速响应以产生IFN和限制 CHIKV感染的循环中的单核细胞，导致病毒传播增强。目的1本提案侧重于表征肠道微生物群指导PDC功能的免疫途径 CHIKV感染。 AIM 2专注于识别由由分子成分（特别是BAS）产生的限制单核细胞和传播的CHIKV感染的特定梭状芽胞杆菌。在一起，这些结果将增强我们对肠道微生物群如何塑造先天免疫反应以限制的理解 α病毒的感染和发病机理，以及可能对单核细胞的向流主义的其他病毒。