Not just acute: IRF-7 has two site-specific functions against chronic gammaherpesvirus infection

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Proposal Summary Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections and are defined by distinct lytic and latent lifecycles. Importantly, human gammaherpesviruses promote a variety of cancers in both immunocompetent and immunocompromised hosts. While risk factors for these virus-driven cancers are poorly understood, it is clear that robust virus-driven germinal center expansion, as well as reactivation of the virus from latency precedes viral oncogenesis. Therefore, host factors that restrict these two processes during infection may represent potential therapeutic targets. Due to the high prevalence and tremendous species specificity of human gammaherpesviruses, the mouse pathogen murine herpesvirus 68 (MHV68) is widely utilized as the small animal model of gammaherpesvirus pathogenesis. A particular strength of this model is the ability to genetically modify the host to examine the cellular and molecular mechanism by which infection is controlled. With this model we have recently identified new and exciting function of the previously underappreciated host factor IRF-7 during gammaherpesvirus infection. Specifically, we found that IRF-7 restricts gammaherpesvirus-driven germinal center expansion at 16 days post infection. Additionally, we found that in the absence of IRF-7, MHV68 reactivates to a greater frequency from peritoneal cells compared to WT. This phenotype was not observed in the spleen. We hypothesize that IRF-7 mediates independent antiviral functions in two separate sites within the host. The in vivo experiments proposed here will provide an extensive, yet focused analysis of the cellular and molecular importance of IRF-7 expression in both the spleen and peritoneal cavity of the host during gammaherpesvirus infection. Importantly, successful completion of these studies will provide insight into the control of gammaherpesvirus infections, which would offer potential therapeutic targets for infected individuals particularly susceptible to the associated oncogenic effects of gammaherpesviruses.