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Abstract

Intestinal commensal microorganisms play a critical role in promoting host health, but these organisms must be carefully managed. Breakdowns in the host’s ability to regulate these commensals can at best result in the loss of these health-promoting functions, and at worst lead to severe inflammation and death. In contrast to host-encoded regulation of bacterial commensals, less is understood about regulation of viral commensals. The so-called virome is increasingly understood to influence host health in both similar and distinct ways to the bacterial microbiome. In this thesis, I utilize the model murine viral commensal MNV CR6 to study host-encoded regulation of viral commensals, as well as the consequences of a failure to regulate these infections. STAT1 has previously been identified as an important host-encoded factor for the regulation of CR6 and other viruses. Using STAT1-deficient mice, I characterize a CR6-induced disease which consists of hyperinflammatory innate and adaptive immune responses, multi-organ inflammatory necrosis, and severe clinical disease requiring euthanasia. STAT1 has previously been shown to protect the host from disease following pathogenic viral infection by limiting the magnitude of T cell responses. However, in CR6 infection, STAT1 instead protects the host from disease by limiting viral replication within responding innate immune cells. Following this, I characterize the complex inflammatory milieu which precedes hepatic necrosis in the absence of STAT1. Environmental perturbations also influence regulation of viral infections. In particular, antibiotic treatment of mice has previously been shown to suppress the generation of antiviral immune responses. While this effect has been ascribed to depletion of the bacterial microbiota, existing evidence also suggests the alternative mechanism of direct effects of antibiotics on host cells. Using germ-free mice, I demonstrate that antibiotic-mediated immunosuppression is microbiota-independent in the context of CR6 infection. Mice treated with an antibiotic cocktail fail to generate virus-specific CD8+ T cells, and my data suggest this effect is mediated though suppression of dendritic cell’s ability to activate T cells. Together, my data describe novel mechanisms influencing the ability of the host to regulate commensal viral infection, and characterizes the consequences of a breakdown in this ability.