Year of Award
2023
Document Type
Dissertation
Degree Type
Doctor of Philosophy (PhD)
Degree Name
Biochemistry & Biophysics
Department or School/College
Division of Biological Sciences
Committee Chair
J. Stephen Lodmell
Commitee Members
Bruce Bowler, Klara Briknarova, Scott Samuels, Scott Wetzel
Publisher
University of Montana
Abstract
Work in this dissertation focuses on how innate immune responses are activated, dysregulated, evaded, and co-opted during Rift Valley fever virus (RVFV) infection. To better understand how innate immune responses are affected during RVFV infection, we placed a particular emphasis on understanding the functions of the atypical kinase RIOK3 in innate immune responses. RIOK3 was previously shown by our group and other groups to be involved in the antiviral type 1 interferon (IFN) and the inflammatory NFκB innate immune responses, but its exact functions in these responses were not clear. Prior research in our group also showed that RIOK3 mRNA is alternatively spliced, primarily to its X2 isoform, which encodes a truncated form of the RIOK3 protein, during infection with RVFV. Therefore, to better understand how innate immune responses are impacted by alternative splicing of RIOK3 during RVFV infection, the work presented here is focused on understanding the roles of both fulllength RIOK3 and RIOK3 X2 in the type 1 IFN and NFκB inflammatory pathways during the cellular innate immune response to infection. We show full-length RIOK3 is important for mounting a type 1 IFN response while simultaneously inhibiting the inflammatory NFκB pathway in epithelial cells. Conversely, alternative splicing of RIOK3 reverses these roles by inhibiting the IFN response and stimulating the NFκB pathway. Furthermore, this work shows alternative splicing of RIOK3 is associated with activation of the noncanonical NFκB pathway, which is an inflammatory NFκB pathway that has been shown to have an inhibitory effect on the type 1 IFN response. We postulate the noncanonical NFκB pathway is co-opted by RVFV to evade the type 1 IFN response. The body of work presented here therefore provides a deeper understanding of how innate immune responses might be dysregulated during RVFV infection and suggests specific mechanisms that underlie this dysregulation.
Recommended Citation
Bisom, Thomas Charles, "REGULATION OF INNATE IMMUNE RESPONSES TO RIFT VALLEY FEVER VIRUS INFECTION THROUGH ALTERNATIVE SPLICING OF RIOK3" (2023). Graduate Student Theses, Dissertations, & Professional Papers. 12214.
https://scholarworks.umt.edu/etd/12214
© Copyright 2023 Thomas Charles Bisom