Date of Award
Doctor of Philosophy (PhD)
The host immune system must constantly function to maintain chronic commensal and pathogenic organisms in check. These organisms include the virome, which is the viral component of the microbiome. The consequences of immune responses to the virome on host physiology are as yet unexplored, and may have long-term implications in health and disease. Here, I used both genetic and infectious mouse models to investigate how the innate antiviral cytokines Type I interferons (IFNs) modulate epithelial turnover. I first found that mice deficient in Irgm1, a p47 GTPase, had persistently elevated Type I IFNs even in the absence of exogenous viral infection. The Irgm1-/- mouse enabled us to study the effects of Type I IFNs on host physiology without the compounding variables imposed by a complex viral infection. I found that Type I IFNs increased epithelial turnover in multiple organs. Chronic viral infection, which induces Type I IFN production, also augmented epithelial turnover, demonstrating the physiological relevance of this process. I discovered that Type I IFNs acted through non-epithelial cells, including macrophages, to promote increased epithelial turnover and wound repair. Downstream of Type I IFN signaling, the highly related IFN-stimulated genes Apolipoprotein L9a and b stimulated epithelial proliferation through ERK activation. These findings demonstrate that the host immune response to chronic viral infection has systemic effects on epithelial turnover through a myeloid-epithelial circuit. This work advances our understanding of the mechanisms that modulate proliferation and cell death of epithelial barriers that provide the first line of protection against the environment.
Chair and Committee
Thaddeus S. Stappenbeck
Marco Colonna, Deborah J. Lenschow, Robert D. Schreiber, William F. Stenson,
Sun, Lulu, "Regulation of Epithelial Turnover by Host-Virome Interactions" (2016). Arts & Sciences Electronic Theses and Dissertations. 763.