Dissertation/Thesis Abstract

Gammaherpesvirus Interactions with Host Germinal Center Responses During Latency
by Owens, Shana M., Ph.D., University of Arkansas for Medical Sciences, 2020, 218; 28000573
Abstract (Summary)

Gammaherpesviruses(GHVs) are cancer-causing viruses that include the human pathogens Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus and the rodent pathogen murine gammaherpesvirus 68 (MHV68). These viruses establish life-long, chronic infections of B cells by driving and usurping polyclonal adaptive immune responses. Promotion of processes that should limit infection is paradoxical and suggests that GHVs guide the adaptive immune response, however, mechanisms used by GHVs to direct adaptive immunity are not known. To address this question and test the hypothesis that latent gene expression alters adaptive immunity, we evaluated immune responses in mice infected with MHV68 as a small-animal model of GHV infection. Using a conditional viral-gene-deletion approach in which viral-gene-product function can be ablated in specific cell types, we found that M2, a latency protein that promotes plasma cell differentiation and viral reactivation, works within GC B cells for viral dissemination and efficient reactivation from latency. Compared to wild-type (WT) MHV68 infection, loss of M2 expression from GC B cells led to significant increases in MHV68-specific adaptive immune responses within lymphoid tissues. Mice infected with M2-deleted virus had morphologically normal B cell follicle development and lymphatic tissue architecture was maintained. Strikingly, WT, but not M2-deleted, MHV68 infections induced high levels of auto-antibody production. These results demonstrate that M2 expression within GC B cells is a key regulator of tissue-specific adaptive immune responses. Furthermore, we evaluated the role of p53, a host tumor suppressor activated by GHV infection, during MHV68 latency establishment and disease. p53 intrinsically restricts early GHV-driven expansion of GC B cells and maintains host genomic integrity following MHV68 infection. In the absence of p53, chronic MHV68 infection promotes disseminated multi-organ lymphoma development. Together, studies presented here demonstrate the complex interplay between viral latency-associated gene products and host responses within the GC during GHV latency establishment and maintenance.

Indexing (document details)
Advisor: Forrest, James C.
Commitee: Boehme, Karl W., Dings, Ruud P. M., Stumhofer, Jason S., Zhang, Xuming
School: University of Arkansas for Medical Sciences
Department: Microbiology and Immunology
School Location: United States -- Arkansas
Source: DAI-B 82/2(E), Dissertation Abstracts International
Subjects: Virology, Immunology
Keywords: Gammaherpesvirus, Latency, M2, Murine gammaherpesvirus 68 (MHV68), p53, vAIDR
Publication Number: 28000573
ISBN: 9798662568938
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