The role of STAT1 signaling in persistent intestinal viral infection

越来越多的数据表明，从微观病毒和细菌到多细胞真核蠕虫寄生虫，寄居在我们肠道中的物种可以对多种生理系统产生强烈影响，包括营养代谢，局部和全身免疫反应，代谢调节和认知功能。然而，我们对这些不同系统如何受肠道定植物种调节的理解存在根本性差距。因此，我的研究计划的首要主题是调查和增加我们对不同物种肠道定植如何影响免疫力和炎症的理解。 本申请的具体目标是解决先天免疫转录因子信号转导子和转录激活子-1（STAT 1）在整合来源于病毒的信号中的作用。STAT 1是宿主对病原体入侵的先天免疫应答的关键组分。病毒感染后，STAT 1作为抗病毒先天免疫的中心枢纽。在识别病毒感染和先天性干扰素诱导后，STAT 1在宿主细胞中被激活并快速诱导干扰素刺激基因的表达。这些信号通路对于限制急性病毒感染后的早期病毒复制至关重要。相比之下，最近的数据表明，慢性病毒感染与持续的1型干扰素信号有关，干扰素信号损害病毒清除。然而，目前还不清楚STAT 1/干扰素信号通路在调节对肠道病毒的应答中的影响。基于我们对微生物组（此处定义为包括病毒和细菌）如何影响如此广泛多样的生理反应的日益认识，必须定义调节这些物种免疫稳态的宿主来源的细胞和分子途径。 使用一个持久的鼠诺如病毒株（MNV），我将测试的假设，即STAT 1是一个关键的调节免疫稳态，是动态参与响应“病毒”。我们预测，这种单一转录因子的消融将导致肠道内外免疫稳态的破坏。这些研究将提供一个框架，通过控制暴露于一种在野生型小鼠中几乎不引起病理的持续性肠道病毒，来创新性地检查宿主来源的细胞和分子相互作用，这些相互作用调节肠道对病毒组的免疫稳态，病毒组是一组在我们肠道中定植的病毒。定义允许宿主响应和调节病毒组的细胞和分子途径将大大增加我们对哺乳动物宿主和病毒组之间的共同进化的理解，该共同进化继续影响哺乳动物生理学的各个方面。

Accumulating data demonstrates that the species that colonize our intestine ranging from microscopic viruses and bacteria up to multicellular eukaryotic helminthic parasites can exert strong influences over multiple physiological systems, including nutrient metabolism, local and systemic immune responses, metabolic regulation and cognitive function. However, fundamental gaps in our understanding of how these diverse systems are regulated by intestinal colonizing species remain. Thus, the overarching theme of my research program is to investigate and increase our understanding of how intestinal colonization with diverse species can influence immunity and inflammation. The specific goal of this application is to address the role of the innate immune transcription factor Signal Transducer and Activator of Transcription-1 (STAT1) in integrating signals derived from a commensal' virus. STAT1 is a critical component of the host innate immune response to pathogen invasion. Following viral infection, STAT1 acts as a central hub of antiviral innate immunity. Following recognition of virus infection and innate interferon induction, STAT1 is activated in host cells and rapidly induces expression of interferon stimulated genes. These signaling pathways are essential to limit early viral replication in response to acute viral infection. In contrast, recent data suggests that chronic viral infection is associated with ongoing type 1 interferon signals that impair viral clearance. However, it is unclear what the impact of the STAT1/interferon signaling pathway is in regulating the response to a commensal' intestinal virus. Based on our increasing appreciation of how the microbiome (defined here to include both viruses and bacteria) influences such a wide diversity of physiological responses, it is imperative to define host-derived cellular and molecular pathways that regulate immune homeostasis to these species. Using a persistent strain of murine norovirus (MNV), I will test the hypothesis that STAT1 is a critical regulator of immune homeostasis that is dynamically engaged in response to 'commensal' viruses. We predict that ablation of this single transcription factor will result in disruptions of immune homeostasis in the gut and beyond. These studies will provide a framework for innovative examination of the host-derived cellular and molecular interactions that regulate intestinal immune homeostasis to the virome', the collection of viruses that colonize our gut, by using controlled exposure to a persistent enteric virus that causes little pathology in wild-type mice. Defining cellular and molecular pathways that allow the the host to respond to and regulate the virome' will greatly increase our understanding of the co-evolution between mammalian hosts and the virome that continues to influence diverse aspects of mammalian physiology.