Enhancing host control of polyomavirus infection
Open Access
- Author:
- Maru, Saumya Yogesh
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 06, 2017
- Committee Members:
- Aron Eliot Lukacher, Dissertation Advisor/Co-Advisor
Aron Eliot Lukacher, Committee Chair/Co-Chair
Todd Schell, Committee Member
Ziaur Rahman, Committee Member
Faoud T Ishmael, Outside Member - Keywords:
- polyomavirus
persistent infection
CD8 T cells
TRM cell
memory CD8 T cell
miRNA
viral miRNA - Abstract:
- Polyomaviruses are small, double-stranded DNA viruses that infect a wide range of host species. Seroprevalence of anti-PyV antibodies in the human population is as high as 90%. These viruses cause subclinical acute infections that are controlled incompletely by an adaptive immune response and thus persist indefinitely in the host, residing primarily in the urogenital tracts and replicating at low levels. The immunocompetent host will shed virus asymptomatically; upon severe immunocompromise, however, uncontrolled viral replication in target organs leads to severe disease. There are currently no effective treatments for polyomavirus infection and no targeted therapies exist. The overall goal of this work is to investigate viral and host determinants of infection to better understand how such persistent viruses are controlled using a mouse model of polyomavirus infection. First, we explore how antigenic stimulation of CD8 T cells impacts the formation and function of a memory response. We demonstrate that low levels of stimulation through the TCR are sufficient to recruit subdominant CD8 T cells to non-lymphoid tissues that establish as tissue residence. Furthermore, lower stimulation of the TCR generates a more potent memory response to secondary infection. Next, we investigate the role of a virally-encoded miRNA. The MuPyV miRNA is complementary to early viral transcripts and thus decreases expression of viral antigens in a presumed immune evasion maneuver. Additionally, we show that the MuPyV miRNA targets multiple members of the TGFβ signaling pathway, suggesting a novel viral mechanism by which cell cycle progression, and thus viral replication, may be enhanced. Third, we address an urgent clinical need and test the efficacy of a potential anti-PyV therapeutic in our mouse model; here we provide the first demonstration of an anti-PyV agent conferring protection in vivo by using an experimental model to mimic the natural course of human PyV-induced diseases. Together, these studies elucidate multiple viral and host determinants of infection that can be exploited to enhance host control of this persistent virus and ultimately decrease morbidity and mortality due to PyV-induced diseases.