Year: 2021
Type: dissertation
Abstract: Viral infections require a delicate balance of pro- and anti-inflammatory factors in order to clear infection while causing minimal immunopathology. A number of coronavirus infections disrupt this balance to cause substantial immunopathology, including JHMV, a neurotropic strain of mouse hepatitis virus, and SARS-CoV-2, the causative agent of COVID-19. My thesis work focused on the various mechanisms by which infected hosts can regulate and resolve these pathogenic immune responses. JHMV causes immunopathology in the central nervous system in the form of immune-mediated demyelination, in which T cells and monocytes/macrophages infiltrate the central nervous system (CNS) to clear viral infection but also cause myelin destruction in the process, leading to disease similar to multiple sclerosis in humans. Microglia, the resident macrophages of the CNS, can play both harmful and beneficial roles during immune-mediated demyelination, but their exact functions are still unclear. Using a drug that depletes microglia, I demonstrated that microglia are essential for repair following the demyelination associated with JHMV infection. I found that microglia play critical roles in initiating the repair process by clearing myelin debris and producing prorepair factors, both of which promote the recruitment and function of oligodendrocytes, the cells responsible for repairing and replacing myelin sheaths. Regulatory T cells (Tregs) play anti-inflammatory roles in a variety of conditions, including in JHMV infection, where they help mitigate immune-mediated demyelination and acute encephalitis by suppressing pathogenic T cell responses and inhibiting inflammatory cytokine production. Most potent at this role are Tregs specific for JHMV epitopes, which are better able to suppress conventional T cells of the same specificity and enter the brain to further inhibit T cell and myeloid cell responses at the site of inflammation. While other virus-specific T cells form memory populations that persist long-term after the resolution of infection and are better able to respond to reinfection, it is unclear if virus-specific Tregs form similar memory responses. Using congenically labeled JHMV-specific Tregs, I found that these cells persist long-term after infection, at least through 180 days post-infection. I additionally demonstrated that they were better able to proliferate after infection than naïve Tregs of the same specificity, suggesting that these Tregs differentiate into memory populations after infection. COVID-19, caused by SARS-CoV-2, can result in severe disease characterized by an exuberant and dysregulated innate immune response that leads to extensive cellular infiltrates in the respiratory tract, ultimately resulting in significant lung pathology. The best available method to prevent this immune-mediated pathogenesis is vaccination against COVID-19, although much is not yet known about optimal vaccine strategies to prevent vaccine breakthrough infections and reinfection. In studying vaccine responses in people that have had and recovered from COVID-19, I found that a single dose of mRNA vaccine resulted in substantial increases in neutralizing antibody responses, significantly more potent than the responses observed in fully vaccinated individuals with no history of COVID-19. Similar results were observed with virus-specific T cell responses, though to a lesser degree than neutralizing antibodies. Strikingly, however, unlike in individuals who did not previously have COVID-19, a second vaccine dose in individuals who recovered from COVID-19 resulted in a decrease in the neutralizing antibody response relative to the first dose, though still greater than the response prior to vaccination. Virus-specific T cell responses were also unaffected following a second vaccine dose, suggesting that an initial single-dose regimen may be optimal for individuals who previously had COVID-19. Overall, these results highlight various means by which protective elements of the host immune response can mitigate immune-mediated pathology in coronavirus infections.
DOI: 10.17077/etd.005851
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4232486260