Immune-mediated antiviral defense against polyomavirus infection of the brain
Open Access
- Author:
- Mockus, Taryn
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- March 15, 2019
- Committee Members:
- Aron Lukacher, Dissertation Advisor/Co-Advisor
Aron Lukacher, Committee Chair/Co-Chair
Ziaur Rahman, Committee Member
Todd Schell, Committee Member
James Connor, Outside Member - Keywords:
- Polyomavirus
T cells
Immunology
Neuroscience
NeuroImmunology - Abstract:
- Progressive multifocal leukoencephalopathy (PML) is an often-fatal demyelinating disease of the brain caused by JC polyomavirus (JCPyV) in immunocompromised individuals. Initially rare, PML has increased in prevalence with the rise of immunomodulatory therapies used for the treatment of autoimmune diseases, many of which impede the movement or function of immune cells. Despite increased incidence, PML pathogenesis remains poorly understood; the only treatment available for PML is to reconstitute the immune response, which can cause immune reconstitution inflammatory syndrome. Most studies of PML to date have utilized post mortem brains of PML patients or immunocompromised humanized mouse models, leaving many unresolved questions regarding the mechanisms of demyelination and the content and contribution of anti-polyomavirus (PyV) immunity. The aim of our work is to provide insight into PyV pathogenesis and defense in the brain using intracerebral (i.c.) infection of immunocompetent mice with mouse polyomavirus (MuPyV), a naturally occurring mouse pathogen, as a novel brain PyV infection model. To this end, we first investigated the contribution of CD4 T cells to the development of antiviral brain-resident CD8 T cells (bTRM). We found that CD4 T cells are required for MuPyV-specific CD8 bTRM development, as demonstrated by decreased expression of canonical tissue-resident memory surface markers, continued dependence on CD8 T cells in the circulation, and decreased ability to control reinfection in CD8 T cells that develop in the absence of CD4 T cells. Furthermore, acquired CD4 T cell deficiency, modeled by delaying systemic CD4 T cell depletion until after the infiltration of MuPyV-specific CD8 T cells into the brain, also impacted the differentiation of CD8 bTRM and decreased the ability of these cells to control reinfection. Together, these findings reveal an intimate association between CD4 T cells and homeostasis of functional CD8 bTRM to brain polyomavirus infection. In conjunction with investigating the nature of the adaptive immune response to MuPyV, we also documented the role of type I, II, and III interferons (IFNs) in anti-PyV defense in the brain. Previous work has shown that IFNs induce an antiviral state in the infected cell and modulate the immune response. We found that type I IFNs mediated viral control during acute brain infection, but no single IFN contributed substantially to PyV control during persistent MuPyV infection. However, mice deficient in signal transducer and activator of transcription 1 (STAT1), the common downstream effector of the IFN family, developed severe hydrocephalus, likely resulting from a loss of intrinsic viral control and a prolonged immune response consisting of inflammatory myeloid cells and polyfunctional CD8 T cells. These findings show that STAT1 is a critical component of the antiviral defense against MuPyV infection. Furthermore, we characterized the infection of brain resident cells and damage following MuPyV infection in the mouse brain. Histological and imaging analysis of MuPyV-infected mouse brains demonstrated histopathological abnormalities similar to those found in PML patients, such as demyelination and infection of glial cells, and a critical role of T cells in preventing PyV encephalitis. Together, our work documents the components of host defense against brain PyV infection and provides insight into the mechanisms of immunological control of PML progression and PyV infection in the brain. A better understanding of polyomavirus infection in the brain is necessary to alleviate the morbidity and mortality that result from polyomavirus-associated diseases.