Regulation of Interferon-Lambda Signaling by Commensal Bacteria and Norovirus

项目摘要/摘要 应聘者：在我的培训中，我非常有动力去了解东道主对 环境，尤其是对致病和共生的细菌和病毒。这一动机促成了 一份成功的出版物记录，代表了对免疫系统如何 对全身和粘膜感染作出反应，并受其控制。我的长期研究目标集中在 确定宿主遗传学和微生物区系影响传染病的机制。 研究生涯发展计划：当我完成我非常成功的研究奖学金与我的 国家公认的宿主专家Virgin博士导师：病原体相互作用，我将利用教育和 在华盛顿大学的研究资源，以加强我的职业发展。我会继续追查下去 接受生物信息学分析和肠道成像方面的培训，并准备过渡到终身教职 通过规划独立调查员的管理和指导责任来确定职位。 研究项目：诺如病毒是一种高传染性病原体，可引起急性胃肠炎和 在人类体内持续的病毒脱落。共生菌在小鼠肠道感染中的前驱体作用 诺如病毒(MNoV)是近年来发现的一种诺如病毒致病的小动物模型。干扰素- 干扰素-λ是一种天然免疫细胞因子，具有很强的抗病毒作用，对人类免疫功能具有重要作用。 调节这种细菌-MNoV的相互作用。然而，共生细菌、MNOV和MNV之间的相互作用 内源性干扰素-λ仍不清楚。该项目建议审问MNOV和共生的作用 细菌在干扰素-λ的诱导下。共生微生物诱导肠道内干扰素刺激基因(ISGs) 以一种依赖于干扰素-λ-受体Ifnlr1的存在的方式。Ifnlr1在上皮细胞中的表达 细胞还调节MNoV的脱落和清除。当肠道上皮细胞对干扰素-λ产生反应时， 产生干扰素-λ的宿主细胞类型对共生菌或MNOV的反应尚不清楚。研究到 定义这种干扰素-λ来源将阐明这种病毒病原体、微生物区系和宿主之间的相互作用 先天免疫系统。细菌和病毒产品，通过模式识别受体作用，刺激 生产IFN。然而，MNOV和共生菌诱导干扰素-λ的调控途径 都是未知的。需要了解内源性干扰素-λ的调节才能揭示持续的NOV 躲避先天免疫系统，可能是通过共生细菌的伪装。这些研究可能会揭示 针对诺沃克病毒感染的新疫苗接种策略或治疗干预措施，这可能会广泛 与其他粘膜病毒相关。干扰素-λ是微生物与细胞间关系的重要调节剂。 宿主肠道，对该分子的研究将为我们提供在粘膜表面进行病原体感染的方法。 这些研究的完成将为未来R01的应用和 在研究病毒病原体、微生物群和宿主免疫系统的相互作用方面取得成功。

PROJECT SUMMARY/ABSTRACT Candidate: During my training, I have been highly motivated to understand the host response to the environment, especially to pathogenic and commensal bacteria and viruses. This motivation has contributed to a successful record of publications, representing advances in the understanding of how the immune system responds to and is regulated by systemic and mucosal infections. My long-term research goals center on defining the mechanisms by which infectious diseases are affected by host genetics and the microbiota. Research Career Development Plan: As I complete my highly successful research fellowship with my mentor Dr. Virgin, a nationally-recognized expert in host:pathogen interactions, I will utilize educational and research resources at Washington University to strengthen my career development. I will pursue further training in bioinformatic analysis and intestinal imaging, and prepare to transition to a tenure-track faculty position by planning for the management and mentorship responsibilities of an independent investigator. Research Project: Noroviruses are highly infectious pathogens that cause acute gastroenteritis and persistent viral shedding in humans. A proviral role for commensal bacteria in intestinal infection by murine norovirus (MNoV), a small animal model for norovirus pathogenesis, was recently uncovered. Interferon- lambda (IFN-λ) is an innate immune cytokine which is potently antiviral against MNoV, and is important for regulating this bacteria-MNoV interaction. However, the interactions between commensal bacteria, MNoV, and endogenous IFN-λ remain unclear. This project proposes to interrogate the role of MNoV and commensal bacteria in IFN-λ induction. Commensal microbes induce IFN-stimulated genes (ISGs) in the intestinal epithelium, in a manner dependent on the presence of the IFN-λ-receptor Ifnlr1. Ifnlr1 expression on epithelial cells also regulates MNoV shedding and clearance. While epithelial cells respond to IFN-λ in the intestine, the host cell type producing IFN-λ in response to commensal bacteria or MNoV remains unknown. Studies to define this IFN-λ source will clarify the interaction between this viral pathogen, the microbiota, and the host innate immune system. Bacterial and viral products, acting through pattern-recognition receptors, stimulate production of IFNs. However, the pathways regulating induction of IFN-λ by MNoV and commensal bacteria are unknown. Understanding the regulation of endogenous IFN-λ is needed to uncover how persistent NoV evades the innate immune system, possibly via cloaking by commensal bacteria. These studies may reveal novel vaccination strategies or therapeutic interventions for norovirus infection, which will likely be broadly relevant to other mucosal viruses. IFN-λ is a critical modulator in the relationship between microbes and the host intestine, and study of this molecule will inform our approach to pathogen infection at mucosal surfaces. Completion of these studies will lay the scientific groundwork for both future R01 applications and for a successful career studying the interactions of viral pathogens, the microbiome and the host immune system.