Dissertation
The central contribution of CD4+ T cells to neurotropic virus control and neuropathogenesis
Doctor of Philosophy (Ph.D.), Drexel University
Mar 2016
DOI:
https://doi.org/10.17918/00010003
Abstract
Infections of cells within the brain can occur following challenge with many viruses and other pathogens. Such infections often result in the activation of parenchymal cells as well as substantial infiltration of blood borne lymphocytes. Recent discoveries reject the notion that the central nervous system (CNS) is "immune privileged". However, it is also true that immune effectors and outcomes are notably different from canonical responses that occur in the periphery. I have investigated the contribution of T cells and B cells in controlling a neuron restricted virus infection, and have discovered that CD4+ T cells play a critical role in immune cell education and consequences following challenge. Specifically, I have shown that survival of permissive mice challenged with measles virus (MV) is CD4+ T cell dependent, but that either B cells or CD8+ T cells must also be present to ensure pathogenesis-free survival. Interestingly, even with an intact immune response, MV RNA is detectable in healthy immune competent adult mice 90-120 days post infection (dpi), suggesting that sterile clearance of infection does not occur in the CNS, allowing the establishment of a life-long subacute infection. In addition, I sought to determine whether the host response to multiple, concurrent antigenic challenges could interact and disrupt the finely tuned balance that occurs in the single neurotropic MV challenge model. To do so, a two virus, tissue-restricted model was developed in which mice are infected with neurotropic MV and viscerotropic lymphocytic choriomeningitis virus (LCMV). Double-infected mice experience a fatal neuropathogenic disease following co-infection, resulting from edema mediated by CD8+ T cells. To better understand how a concurrent immune response could alter a non-pathogenic MV response in the brain, I used an adoptive transfer approach, and showed that, while CD8+ T cells are necessary for pathogenesis, they are not sufficient. Rather, CD4+ T cells, activated by an allogeneic immune challenge, appear to "convert" MV-specific CD8+ T cells to a neuropathogenic phenotype. Taken together, these results further dissect the complex interplay of T lymphocytes following neurotropic virus infection, and have revealed novel pathogenic mechanisms that occur in the CNS following polymicrobial challenge
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Details
- Title
- The central contribution of CD4+ T cells to neurotropic virus control and neuropathogenesis
- Creators
- Andreas Constantine Solomos
- Contributors
- Glenn Rall (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xii, 130 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021888961904721