Gut Microbiota Modulation of Chikungunya Virus Infection and Pathogenesis

基孔肯雅病毒感染和发病机制的肠道微生物群调节

• 批准号: 10597063
• 负责人: Michael S Diamond
• 金额: $ 66.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597063
• 关键词: Acute; Adoptive Transfer; Affect; Age; Alphavirus; Alphavirus Infections; Antibiotics; Antiviral Agents; Antiviral Response; Arthritis; Bacteroides; Bile Acids; Blood; Bone Marrow; Butyrates; CD80 gene; CD86 gene; Cells; Chikungunya virus; Chronic; Chronic Disease; Circulation; Clinical Trials; Clostridium; Cues; Culicidae; Data; Dendritic Cells; Diamond; Disease; Disease Progression; Epidemic; Focal Infection; Genetic; Germ-Free; Goals; House mice; Human; Immune; Immune response; Immunity; Immunologics; Infection; Infiltration; Inflammation; Inflammatory Response; Innate Immune Response; Interferon Type I; Interferons; Joints; Knockout Mice; Licensing; Link; Mediating; Metabolic; Metagenomics; Microbe; Molecular; Morbidity - disease rate; Mus; Musculoskeletal; Musculoskeletal Diseases; Natural Immunity; Oral; Pathogenesis; Persons; Phylogenetic Analysis; Polyarthritides; Prevention; Production; Research Personnel; Risk; Role; Severities; Shapes; Signal Transduction; Site; TLR7 gene; TNF gene; Testing; Tissues; Transgenic Mice; Vaccines; Viral; Viral Load result; Viral Pathogenesis; Viremia; Virus; Virus Diseases; Virus Replication; Volatile Fatty Acids; acquired factor; arginase; arthropathies; chikungunya infection; commensal bacteria; experimental study; fecal transplantation; gut bacteria; gut microbiota; human disease; immune cell infiltrate; immunological status; joint inflammation; microbial; microbiome; microbiota; migration; monocyte; multidisciplinary; mutant; novel therapeutics; oral supplementation; prevent; receptor; reconstitution; response; trafficking; transmission process; vector mosquito

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.

项目摘要 Chikungunya病毒（CHIKV）是蚊子传播的，正链包膜的α病毒，导致全球 人类疾病。目前，尚无抗病毒剂或许可疫苗以治疗或预防 任何α病毒感染。年龄，免疫状态和先前存在的慢性病与 严重CHIKV感染的风险增加，获得的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 通过先前未定义的轴炎症和疾病，肠道细菌和胆汁酸信号 指导先天免疫细胞反应以控制循环和单核细胞中单核细胞的CHIKV感染 迁移到受影响的关节组织。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I型IFN和炎症反应来调节CHIKV发病机理 单核细胞。在没有这些微生物信号的情况下，ChikV广泛传播，关节炎随后发生 免疫细胞关节浸润。该建议将研究人员与α病毒发病机理的专业知识相结合 和免疫（钻石）以及疾病肠道菌群（Handley，Stappenbeck和Fischbach）的研究。 使用一套转基因小鼠和微生物重建实验与详细的病毒学和 免疫学分析，我们将解决以下关键问题：（a）免疫细胞协调 CHIKV感染后快速的全身IFN反应（例如PDC）（b）什么免疫提示限制了病毒感染 循环中的免疫细胞（例如，单核细胞）？ （c）肠道菌群如何调节PDC IFN产生和 运输循环免疫细胞？ （d）微生物群的哪些成分（例如代谢产物） 抗病毒和炎症反应？通过这些详细的机械研究，我们希望将 特定的共生细菌的微生物衍生成分，其先天抗病毒反应调节 α病毒感染，传播，关节疾病以及可能的传播。超越我们的 了解α病毒发病机理的获得的决定因素，该提案的发现可以告知 更一般地，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 和其他病毒的发病机理。