The role of STAT1 signaling in persistent intestinal viral infection

越来越多的数据表明，定植于我们肠道的物种--从微小的病毒和细菌到多细胞真核寄生虫--可以对多种生理系统产生强烈的影响，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，在我们对肠道定植物种如何调控这些不同系统的理解中，仍然存在根本的差距。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的肠道定植如何影响免疫和炎症的理解。 本申请的具体目标是解决先天免疫转录因子信号转导和转录激活因子-1(STAT1)在整合来自‘共生’病毒的信号方面的作用。STAT1是宿主对病原体入侵的先天免疫反应的重要组成部分。在病毒感染之后，STAT1起到了抗病毒天然免疫的中枢作用。在识别病毒感染和先天干扰素诱导后，STAT1在宿主细胞中被激活，并迅速诱导干扰素刺激基因的表达。这些信号通路对于限制病毒的早期复制以应对急性病毒感染至关重要。相比之下，最近的数据表明，慢性病毒感染与正在进行的1型干扰素信号有关，这种信号损害了病毒的清除。然而，目前还不清楚STAT1/干扰素信号通路在调节对‘共生’肠道病毒的反应方面有什么影响。基于我们对微生物组(这里定义包括病毒和细菌)如何影响如此广泛的多样化生理反应的日益认识，定义宿主衍生的细胞和分子途径来调节这些物种的免疫动态平衡是当务之急。 使用一种持久的小鼠诺如病毒株(MNV)，我将测试STAT1是免疫稳态的关键调节器的假设，该调节器动态地参与对共生病毒的反应。我们预测，去除这个单一的转录因子将导致肠道内和肠道以外的免疫动态平衡被破坏。这些研究将提供一个框架，对宿主衍生的细胞和分子相互作用进行创新检查，通过控制暴露于一种对野生型小鼠几乎不会造成病理变化的持久性肠道病毒，来调节肠道免疫动态平衡。确定允许宿主响应和调节‘病毒体’的细胞和分子途径将极大地提高我们对哺乳动物宿主和继续影响哺乳动物生理的不同方面的病毒体之间的协同进化的理解。

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.