Norovirus regulation via bacterial modulation of interferon-lambda

通过细菌调节干扰素-λ来调节诺如病毒

• 批准号: 10356068
• 负责人: Megan T Baldridge
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356068
• 关键词: Acute; Animal Model; Automobile Driving; Bacteria; Bacterial Infections; Bacteroides; Biological Assay; Cell Communication; Cell Culture System; Cell model; Cells; Characteristics; Childhood; Chronic; Data; Defect; Developing Countries; Development; Disease Outbreaks; Enteral; Enterocytes; Epidemic; Epithelial Cells; Future; Gastroenteritis; Genetic Transcription; Goals; Human; Immune; Immune signaling; Immune system; Immunocompromised Host; Immunologic Factors; In Vitro; Incidence; Infection; Infection prevention; Inflammation; Interferon Receptor; Interferons; Intestines; Materials Testing; Mediating; Metabolic; Microbe; Modeling; Mus; Norovirus; Phenotype; Play; Prevention; Probiotics; Process; Production; Rag1 Mouse; Regulation; Reporter; Resistance; Role; Rotavirus; Rotavirus Infections; Seeds; Severities; Signal Transduction; Stomach; System; Testing; Transfer Factor; Up-Regulation; Vaccine Therapy; Vaccines; Viral; Virus; Virus Diseases; Wild Type Mouse; adaptive immunity; bacteriome; base; cell growth regulation; combat; commensal bacteria; cytokine; dysbiosis; enteric infection; enteric virus infection; experimental study; fecal transplantation; flu; gut inflammation; immunoregulation; in vitro activity; in vivo; intestinal epithelium; microbial; microbial community; microbiome; mortality; mouse model; novel; oral vaccine; pathogen; prevent; probiotic therapy; receptor; response; trait; transcription factor; viral resistance; viral transmission

PROJECT SUMMARY/ABSTRACT Norovirus is the leading cause of epidemic gastroenteritis worldwide, but lacks an effective vaccine or antiviral treatment. After infection, virus can be shed chronically for weeks to months, potentially contributing to future outbreaks. A small animal model for persistent norovirus infection revealed that the commensal bacterial microbiome enhances norovirus infection. Interferon-lambda (IFN-λ), an innate immune cytokine, plays an important role in this process via an unclear mechanism. IFN-λ stimulates antiviral signaling on intestinal epithelial cells, the same cells infected by persistent norovirus in vivo, and can prevent or cure infection. Commensal bacteria may therefore promote norovirus infection by preventing host IFN-λ responses to virus. Recent data also revealed that altered microbial communities in immunocompromised mice are associated with excessive IFN-λ and norovirus resistance. A unifying hypothesis for these findings is that specific bacteria diminish or enhance the capacity of intestinal epithelial cells to generate IFN-λ to regulate norovirus. Identification of specific commensal bacteria that promote norovirus is critical to understanding in vivo viral regulation. Dilutional fecal transplants and colonization experiments revealed a promising bacterial candidate; comparison of this candidate to a related species that does not promote norovirus will highlight bacterial phenotypic characteristics determining viral infection. The effects of this bacteria on specific metabolites, as well as assessment of its localization in proximity to norovirus-infected cells in vivo, will be explored. This proposal will also evaluate how this candidate bacteria regulates norovirus-permissive tuft cells. Preliminary data indicates that bacterial products prevent IFN-λ induction by norovirus in vitro. Reporter mice will be used to assay in vivo regulation of interferon signaling and viral infection by bacteria. The mechanisms by which bacteria alter transcriptional responses to virus will also be interrogated in a novel in vitro intestinal epithelial cell model. Finally, a fecal factor in immunocompromised mice confers norovirus resistance when transferred, and correlates with excessive IFN-λ and altered intestinal bacteria. The role of IFN-λ in this viral resistance will be tested using mouse lines lacking the IFN-λ-receptor, and the transferable factor will be identified by treating transferred material and testing candidate isolates. Because the immunocompromised mice have broad adaptive immune defects, different adaptive immune factors will be tested for their regulation of the microbiome and the transferable factor. Completion of this proposal will provide mechanistic understanding into the regulation of intestinal innate immune signaling and norovirus infection by commensal bacteria. These studies will reveal bacteria with modulatory effects on the intestinal epithelium to adapt for probiotic strategies to combat enteric viruses.

项目摘要/摘要 诺如病毒是全球流行胃炎的主要原因，但缺乏有效的疫苗或 抗病毒治疗。感染后，病毒可以长期脱落数周至数月，有可能导致 未来爆发。持续性诺如病毒感染的小动物模型表明，共生细菌 微生物组增强了诺如病毒感染。 Interferon-Lambda（IFN-λ），一种先天免疫细胞因子，发挥 通过不清楚的机制在此过程中的重要作用。 IFN-λ刺激肠上的抗病毒信号传导 上皮细胞，体内持续性诺如病毒感染的相同细胞，可以预防或治愈感染。 因此，共生细菌可以通过防止宿主IFN-λ对病毒的反应来促进诺如病毒感染。 最近的数据还显示，免疫功能低下的小鼠中的微生物群落改变与 过度的IFN-λ和诺如病毒抗性。这些发现的统一假设是特定细菌 减小或增强肠上皮细胞产生IFN-λ的能力，以调节诺如病毒。 鉴定促进诺如病毒的特定共生细菌对于理解体内至关重要 病毒调节。稀释的粪便移植和定殖实验显示出有希望的细菌 候选人;该候选人与不促进诺如病毒的相关物种的比较将突出显示 细菌表型特征决定病毒感染。该细菌对特定的影响 代谢产物以及对诺如病毒感染细胞接近体内的定位的评估，将是 探索。该建议还将评估该候选细菌如何调节诺如病毒 - 验证簇细胞。 初步数据表明，细菌产物可以预防诺如病毒在体外诱导的IFN-λ诱导。记者老鼠会 被用来断言细菌对干扰素信号传导和病毒感染的体内调节。这些机制 哪些细菌改变对病毒的转录反应也将在新型的体外肠道中受到质疑 上皮细胞模型。最后，免疫功能低下的小鼠的粪便因素在 转移，与过量的IFN-λ和肠细菌改变。 IFN-λ在该病毒中的作用 电阻将使用缺乏IFN-λ受体的小鼠线进行测试，可转移因子将为 通过处理转移的材料和测试候选分离株来识别。因为免疫功能低下的小鼠 具有广泛的适应性免疫障碍，将测试不同的适应性免疫因子因其调节 微生物组和转移因子。 该提案的完成将为肠道的调节提供机械理解 共生细菌的免疫信号传导和诺如病毒感染。这些研究将揭示细菌与 对肠上皮的调节作用，以适应益生菌策略以对抗肠道病毒。