M2 and Blimp-1: Studies in murine gammaherpesvirus 68 pathogenesis and B cell biology

Gammaherpesviruses establish life-long infections in lymphcytes and are associated with a variety of lymphomas and carcinomas. The murine gammaherpesvirus68 (MHV68), which naturally infects wild murid rodents, has emerged as a model pathogen to study latency and reactivation in vivo. MHV68 latently infects B cells, dendritic cells, and macrophages; the long-term latency reservoir is the memory B cell. This thesis explores the role of B cells in MHV68 latency from both the pathogen and host viewpoint. Firstly, I examined how M2, a latency-associated MHV68 gene product, manipulates B cell biology to enable MHV68 to establish and reactivate from latency. I demonstrate that M2 expression in primary murine B cells leads to B cell proliferation, survival, and differentiation into an activated, pre-plasma memory B cell phenotype. M2-driven proliferation is dependent on IL-10, and M2 expression during MHV68 infection is associated with a significant increase in serum IL-10 levels at the onset of latency. Secondly, I studied the role of B-lymphocyte induced maturation protein-1 (Blimp-1), the master transcriptional regulator of plasma cell differentiation, in MHV68 pathogenesis in vivo. I observed that Blimp-1 expression in infected cells plays a significant role in the establishment of latency and reactivation from latency. Additionally, Blimp-1 expression in splenocytes is needed for the maintenance of MHV68 long-term latency. Together, these studies of M2 and Blimp-1 demonstrate how the biology of the B cell is intertwined with MHV68 pathogenesis.