Characterizing the role of interferons in host-microbe interactions in disseminated murine norovirus infection and steady-state hematopoiesis
Date of Award
Doctor of Philosophy (PhD)
Interferons are critical cytokines responsible for regulating host-microbe interactions in the context of infectious disease as well as homeostatic interactions with the host’s native microbiota. Although significant knowledge regarding the role of interferons in these interactions has been gained in the past sixty years, the diversity of microbes with which the host interacts and the plethora of interferons (with over twenty distinct cytokines organized into three types, based on their receptor utilization) which the host uses in these responses leads to a significant number of interactions which remain to be characterized. Here, we further dissect the role of interferons in regulating infection with avirulent and pathogenic strains of murine norovirus as well as during homeostasis as key intermediates between the gut microbiota and hematopoiesis. From these, we uncover roles for all three types of interferons in restricting infection of diverse body sites during infection, primarily by restricting norovirus cell tropism to distinct epithelial or lymphoid populations. We also identify intriguing pro-viral roles for type I and II interferons in enteric murine norovirus infections, in an exciting example of non-canonical roles for these primarily anti-viral cytokines. Additionally, we demonstrate that the microbiota produces a variety of metabolites which promote systemic interferon signaling to drive steady-state hematopoiesis. In particular, we provide evidence for a role of the gut microbiota in providing pro-survival signals for circulating lymphoid cells, without which peripheral lymphocytes and bone marrow B progenitors are rapidly depleted. Together, these findings expand our knowledge of the role of interferons in homeostasis and disease, improve our understanding of viral factors underlying distinct pathogenic or avirulent viral lifestyles, and identify new pathways underlying the regulation of hematopoiesis.
Chair and Committee
Megan T. Baldridge
Deborah J. Lenschow
Walker, Forrest, "Characterizing the role of interferons in host-microbe interactions in disseminated murine norovirus infection and steady-state hematopoiesis" (2022). Arts & Sciences Electronic Theses and Dissertations. 2728.
Available for download on Saturday, May 04, 2024