Date of Award
Doctor of Philosophy (PhD)
The mammalian gut is a complex organ which changes over the course of development and is influenced by the presence of a dense community of gut-resident microbes. Enteric viruses infect the gastrointestinal tract in the context of the commensal microbiota and host immunity. Here, we dissect the influence of host developmental stage and the gut microbiota in norovirus infection. From this work, we determine that murine norovirus (MNoV) infection in early life is restricted by an absence of the target MNoV cell tuft cells and intact interferon (IFN) signaling. However, viral inoculum taken up by non-specific endocytosis in the neonatal ileum leads to prolonged detection of viral RNA and development of immune responses even in the absence of infection in immunocompetent neonates. In the absence of IFN responses, neonates are susceptible to replicative infection, viral dissemination, and lethality. We further identify a single microbe, Bacteroides ovatus, which is sufficient to enable persistent MNoV infection in adult mice, which are unable to be infected in the absence of a bacterial microbiota. Although B. ovatus produces the metabolite succinate in the gut, a metabolite which expands tuft cell populations, this is unexpectedly not the mechanism by which B. ovatus rescues enables MNoV infection in adult mice. Additionally, we demonstrate that loss of type III IFNs recapitulates loss of the type III IFN receptor in the control of viral infection at mucosal surfaces with generation of an Ifnl2-/-Ifnl3-/- knockout mouse which lacks all type III IFN cytokine production. Finally, we describe the progression of microbiota maturation in neonatal mice from the preweaning period through maturation to adults. Together, these data demonstrate the importance of considering gut developmental stage, immune control, and commensal microbiota in regulating enteric virus outcome.
Chair and Committee
Megan T. Baldridge
Adrianus Boon, Misty Good, Andrew L. Kau, Carolina B. López,
Kennedy, Elizabeth Alexandra, "Host development and microbiota influences on norovirus infection" (2022). Arts & Sciences Electronic Theses and Dissertations. 2800.
Available for download on Friday, December 15, 2023