The proviral role of B cell-intrinsic IL-17RA signaling in the establishment of chronic gammaherpesvirus infection

Abstract

Epstein-Barr virus (EBV) is a human specific gammaherpesvirus that establishes lifelong infection in >95% of all adults and is associated with multiple cancers, including B cell lymphomas. Murine gammaherpesvirus 68 (MHV68) is a natural rodent pathogen that is genetically and biologically related to EBV and importantly provides a tractable animal model to study viral and host factors that impact chronic infection. Both of these viruses have a natural tropism for B cells and usurp B cell differentiation to drive a robust polyclonal germinal center response, which is needed to establish the latent viral reservoir in memory B cells. The factors which these viruses use to usurp the host germinal center response to establish chronic infection are not clearly defined. Using MHV68 we discovered that global IL-17RA signaling as well as T-cell intrinsic IL-17RA signaling is proviral and supports the gammaherpesvirus-driven germinal center response needed to establish chronic infection. Loss of global and T-cell intrinsic IL-17RA signaling resulted in a significant attenuation in the germinal center response as well as viral latency and reactivation. Given the B cell tropism of MHV68 we generated a B cell specific model of IL-17RA deficiency to understand the significance of IL-17RA signaling in virally infected cells. Loss of IL-17RA signaling in B cells during MHV68 infection resulted in an attenuated germinal center response as well as reduced viral reactivation and latency, similar to what was observed in the loss of global and T-cell intrinsic IL-17RA signaling. This indicates that IL-17RA signaling in both virally infected and uninfected cells play an important proviral role in the establishment of chronic gammaherpesvirus infection. WMed Start up funds and an American Cancer Society Postdoctoral Award (134165-PF-19-176-01-MPC) which was used to generate the B cell specific IL-17RA deficient mice.