Date of Award
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Cellular, Molecular and Biomedical Sciences
First Advisor
Dimitry N. Krementsov
Abstract
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), that represents the most common non-traumatic neurological disease of young adults. Significant heterogeneity in both disease presentation and severity exists. The etiology of MS is multifactorial, implicating both environmental and genetic factors. Perhaps the most robust environmental contributor is infection with the gammaherpesvirus Epstein-Barr Virus (EBV), which has been shown to increase the risk of developing MS ~20 fold. However, EBV infection is nearly ubiquitous in the human population unlike the occurrence of MS, revealing an unknown mechanism for the association of EBV and increased MS risk. Similarly, genetic studies have identified numerous loci associated with MS susceptibility. However, genetic contributors to disease heterogeneity, while distinct from MS susceptibility, remain elusive. To address these gaps in knowledge, mouse models leveraging aspects of genetic diversity were utilized. Given the ubiquitous nature of EBV, it has been suggested that poor control of the virus (amongst other things) could explain why only a subset of EBV+ individuals develop MS. To assess the role of host genetic variation in the regulation of immune responses to gammaherpesvirus infection, we infected C57BL/6J (B6) and wild-derived PWD/PhJ (PWD) mice with murine gammaherpesvirus-68 (MHV-68), a gammaherpesvirus similar to EBV. Given the central role of CD4 T cells in MS, we determined the effect of latent MHV-68 infection on the CD4 T cell transcriptome. Chronic MHV-68 infection in B6, but not PWD, mice resulted in an upregulation of genes characteristic of cytotoxic T helper cells (ThCTLs), a subset that’s also implicated in MS. Analysis of MHV-68 replication demonstrated that PWD mice had superior control of viral load, which was not attributable to cell-intrinsic resistance to infection but was mediated by NK cells. Taken together, these findings demonstrate that host genetic variation can regulate gammaherpesvirus replication through disparate immunological mechanisms and suggest a mechanism by which genetically determined poor control of gammaherpesvirus can result in an increased risk of MS via immunological skewing associated with augmented ThCTL responses. To examine the genetic basis of MS disease heterogeneity, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and the immune-mediated model of MS, experimental autoimmune encephalomyelitis (EAE). The 32 CC strains studied captured a wide spectrum of EAE severity, progression, and disease course phenotypes, in addition to sex differences, reminiscent of the human disease. Profiling of CNS infiltrating cells and histology revealed distinct pathology associated with clinically relevant disease phenotypes. Quantitative trait locus analysis revealed distinct genetic linkage patterns for different EAE phenotypes, with loci for both EAE severity and incidence of atypical axial rotary (AR)-EAE passing 20% genome wide significance. Machine learning-based approaches prioritized candidate genes for loci underlying EAE phenotypes, including EAE severity (Abcc4 and Gpc6) and AR-EAE (Yap1 and Dync2h1). This work expands the EAE phenotypic repertoire and identifies novel loci controlling unique EAE phenotypes, supporting the hypothesis that heterogeneity in MS disease course is driven by genetic variation. Taken together, the work presented in this dissertation suggest that genetic variation is a crucial determinant of both gammaherpesvirus infection outcomes and MS/EAE disease heterogeneity and illustrates the importance of considering genetic variation in animal models of complex trait human diseases.
Language
en
Number of Pages
245 p.
Recommended Citation
Nelson, Emily, "Through The Lens Of Genetics: Impact Of Genetic Variation On Gammaherpesvirus Infection Outcomes And Multiple Sclerosis Disease Heterogenity" (2025). Graduate College Dissertations and Theses. 2013.
https://scholarworks.uvm.edu/graddis/2013
Included in
Genetics Commons, Immunology and Infectious Disease Commons, Nanoscience and Nanotechnology Commons
