Establishing the impact of roseolovirues on development of autoimmunity due to loss of central tolerance

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Project Summary Murine roseolovirus (MRV) is a beta-herpesvirus that is genetically highly related to the human roseoloviruses, HHV-6 and HHV-7. The human roseoloviruses have been associated with autoimmune disease but demonstrating causality is confounded by the ubiquitous and chronic nature of roseolovirus infections. We have shown that neonatal MRV infection results in transient thymic and peripheral CD4+T cell depletion. Interestingly, we found that neonatal MRV infection leads to development of autoimmune gastritis (AIG) in adult mice, in the absence of active MRV replication. In our preliminary studies, we demonstrated that neonatal MRV infection resulted in a transient decrease in medullary thymic epithelial cells (mTECs) as well as reduced expression of AIRE and tissue restricted self-antigens in the thymus. Moreover, MRV appears to directly infect mTECs, suggesting a potential mechanism for MRV-induced autoimmunity. Indeed, neonatal MRV infection results in development of autoreactive CD4+ T cells that are necessary and sufficient for MRV-induced AIG. Our preliminary data suggest that roseoloviruses can induce autoimmunity by disrupting central tolerance. The broad goal of this proposal is to define the mechanism by which roseoloviruses induces autoimmune disease through its impact on central tolerance. We intend to meet this goal by, first defining the impact of human and murine roseolovirus on mTECs. This will be done by delineating mTEC transcriptomic changes that occur after MRV infection in vivo and by MRV and human roseolovirus infection in vitro. Second, we will establish the impact of MRV on TCR repertoire and neonatal CD4+ T cells. We will evaluate the impact of MRV on TCR repertoire over time by using TCR sequencing, while neonatal CD4+ T cell studies will utilize lineage tracing as well as in vivo and in vitro functional assays. My overall career goal is to understand the interaction between viruses and the immune system, especially in regard to autoimmunity. This five-year K08 Mentored Clinical Scientist Research Career Development Award will allow me to begin my transition of the proposed research project toward one that will be pursued independently. The overall scope of this research is broad, with multiple future directions that can be pursued during my career. By carrying out the Aims of this proposal as well as the career development goals, I will be able to establish myself as an independent physician-scientist and make significant contributions to the fields of viral immunology and autoimmunity.