Gammaherpesvirus and IL-17: using host antibacterial defense to benefit chronic virus infection

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Abstract Gammaherpesviruses establish infection in >95% of adults and are associated with multiple cancers, including B cell lymphomas. These viruses usurp B cell differentiation by infecting naïve B cells and driving entry of latently infected and bystander B cells into a germinal center response to ultimately achieve life-long latency in memory B cells. Importantly, the germinal center response is highly mutagenic and is thought to be the target of viral transformation. The mechanisms by which gammaherpesviruses usurp B cell differentiation, including germinal center response, are largely unknown. This proposal is based on our discovery that IL-17A selectively promotes the gammaherpesvirus-driven germinal center response and viral reactivation, two processes that are associated with increased risk of viral lymphomagenesis. IL-17A is induced by and contributes to the clearance of bacterial and fungal pathogens, with our studies revealing an unexpected proviral role of this cytokine. The proposed studies test the hypothesis that natural induction of IL-17A by bacterial pathogens is usurped by gammaherpesviruses to promote germinal center response and viral reactivation. The proposed studies will determine the extent to which a systemic or anatomically restricted bacterial infection impacts gammaherpesvirus-driven germinal center response and viral reactivation and use host and bacterial genetics to define the role of IL-17A in this process. Successful completion of the proposed studies will for the first time define the impact of natural IL-17A induction by common bacterial pathogens on the key pathogenic processes associated with viral lymphomagenesis and will provide insight into novel approaches to target susceptibility to virus-driven lymphomas.