The role of STAT1 signaling in persistent intestinal viral infection

点击翻译按钮获取中文摘要

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.