Modeling chronic gammaherpesvirus infection as a risk factor for MS reveals a profound impact of host genotype on control of viral load and T helper reprogramming

Abstract

Abstract Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that impacts approximately 2 million people worldwide. The etiology of the disease is multifactorial, consisting of multiple environmental and genetic risk factors. A major risk factor is chronic infection with the gammaherpesvirus, Epstein Barr Virus (EBV). The mechanisms by which EBV increases MS risk, including the role of host genetics, are still unclear. To examine the role of host genetics on gammaherpesvirus infection outcomes, we infected male and female C57BL/6 (B6) and wild-derived PWD/PhJ (PWD) mice with MHV-68, a gammaherpesvirus homologous to EBV. Given the central role of CD4 T cells in MS, we first determined the effect of latent gammaherpesvirus infection on the CD4 T cell transcriptome. CD4 T helper cells were isolated from chronically infected mice followed by transcriptional profiling. Chronic MHV-68 infection resulted in a dramatic upregulation of genes characteristic of so-called cytotoxic T helper cell (ThCTL) phenotypes, including Gzmb, Cx3cr1, Klrg1, Prdm1, and Tbx21, which was most pronounced in B6 females, and highly muted in PWD mice of either sex. Flow cytometric analyses confirmed the genotype-specific expansion of ThCTL-like cells, beginning within 9 days of infection and continued into latency. Analysis of MHV-68 replication kinetics demonstrated that PWD mice had remarkably superior control of viral load early and late in infection. Because poor control of EBV viral load and enhanced anti-EBV responses are associated with greater MS risk, taken together, our findings suggest that the increased risk of MS due to EBV infection might be due to genetically determined poor control of viral load and augmented ThCTL responses. Supported by a grant from the NIH (R21 NS095007)