Determining the relationship between Epstein-Barr virus and multiple sclerosis using a mouse model

Multiple Sclerosis (MS) is caused by a combination of genetic and environmental factors. It is believed that previous infection with Epstein Barr Virus (EBV) plays an important role in the development of MS. To examine this, our lab developed a murine model where latent infection with gamma herpesvirus 68 (γHV-68), the murine homolog to EBV, enhanced the symptoms of experimental autoimmune encephalomyelitis (EAE), resulting in disease that more closely resembles MS development in humans. Latency of γHV-68 primarily occurs in memory B cells. Here, we explored which conditions were necessary for EAE enhancement. We showed that latently infected memory B cells were capable of enhancing EAE symptoms when transferred from mice infected with γHV-68 into uninfected mice. We observed a prevention of enhancement when B cells were depleted before infection. However, depletion after the establishment of latency only partially reduced EAE. This indicated the existence of a mechanism where B cells likely play an important role as antigen presenting cells (APCs) prior to EAE induction for the priming of Th1 cells, and that these signals persist in the mouse even after B cell depletion. Using RNAseq analysis we identified 22 genes that differ between B cells from infected versus uninfected mice. Upon the establishment of latency, CD11b+CD11c+ cells show upregulation of CD40 and pSTAT1. This suggests a contribution by type I IFNs in EAE enhancement. To test this, we used IFNARko mice, however, there was no difference in EAE enhancement, suggesting that while type I IFNS are relevant for maintenance of latency and antiviral responses, they are not contributing to EAE exacerbation. Finally, while infection of mice at a young age did not result in EAE enhancement, infection in adult mice left a long-lasting immune impact that directed enhanced autoimmunity even after 5 months of latent infection. Based on these results we propose a mechanism for how gammaherpesviruses contribute to the development of autoimmunity and suggest that cells infected with EBV can be the target of new therapeutic treatments that would be highly effective and less damaging to the immune system of MS patients.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat