Doctor of Philosophy (PhD)
Human cytomegalovirus (HCMV) is a widespread, highly prevalent pathogen with severe consequences in vulnerable populations. HCMV and the related murine cytomegalovirus (MCMV) encode multiple G protein-coupled receptor (GPCR) homologs which are involved in latency, immune evasion, and tissue tropism and dissemination. In this work, we investigate the mechanisms of two CMV-encoded GPCR homologs, HCMV US28 and MCMV M33, in latency and T cell immune evasion. Chapter 2 describes the isolation and immortalization of a salivary gland-derived mesenchymal cell line, termed mSGM. These cells are permissive to MCMV infection and express all three BALB/c mouse MHC class I isotypes, making them a valuable tool for subsequent studies. Chapter 3 describes the immune repercussions of infection with an M33-deficient virus, DM33stop. It is demonstrated in these studies that M33 is responsible for modulation of T cell responses during both acute and latent MCMV infection, that it inhibits host cell apoptosis, and that it alters major histocompatibility complex (MHC) class I expression on the cell surface. It is further shown that DM33stop does not reactivate efficiently from latency in vivo in B cell-deficient, T cell-depleted mice, indicating that M33 is also involved in reactivation in the absence of lymphocyte immune control. Remarkably, mice infected with DM33stop undergo T cell memory inflation with only one of the two described BALB/c T cell epitopes, indicating a previously unknown role of M33 in immune responses to latent MCMV and dramatically altering the accepted model of memory inflation. Collectively, these results bring to light new insights into the pleiotropic roles of viral GPCRs in latency and immune control, which may lead to the development of new drugs and immunotherapies for the treatment of HCMV disease.
White, Timothy, "Novel Roles for Viral GPCRs in CMV Latency and Immunity" (2022). LSU Doctoral Dissertations. 5776.
Cardin, Rhonda D.
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