Biology and Biomedical Sciences: Molecular Microbiology and Microbial Pathogenesis
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
Deborah J Lenschow
ISG15 is a diubiquitin-like posttranslational modifier and one of the most rapidly induced genes upon type I interferon stimulation. Hundreds of host proteins have been identified as targets of ISG15 conjugation after interferon stimulation, and a number of viral proteins have been shown to be modified by ISG15 during infection. Given the known importance of posttranslational protein modification in the regulation of cellular biology, understanding how ISG15 affects the interferon response and virus replication has been of considerable interest. ISG15 deficient mice have previously been shown to exhibit increased susceptibility to a number of different viruses, including influenza A and influenza B viruses. In these studies we set out to characterize how ISG15 mediates protection against respiratory virus infections. ISG15 conjugation has been shown to inhibit influenza B virus propagation in vivo, however the mechanism by which it reduces viral loads has not been determined. Here we show that ISG15 can inhibit virus replication in a primary trachea epithelial cell culture, suggesting that ISG15 can directly antagonize some step of the virus lifecycle. Furthermore, increasing ISG15 conjugation through inhibition of the ISG15 deconjugating enzyme, UBP43, promotes increased antiviral activity against influenza B virus. Interestingly, increasing the pool of ISG15 conjugates in this manner results in an upregulation of interferon stimulated gene expression, demonstrating a previously undescribed role of ISG15 deconjugation in dampening the interferon response. We found that ISG15 also protects mice from influenza A virus and Sendai virus induced lethality by a conjugation dependent mechanism. However, in these infection models, ISG15 conjugation had little effect on virus burden in vivo or virus replication in tissue culture. We also did not observe any major differences in the acute immune response of ISG15 deficient mice after infection. These results demonstrate a novel non-antiviral role for ISG15 conjugation in promoting survival after viral infection.
Morales, David James, "Dual Roles of Interferon Stimulated Gene-15 During Respiratory Virus Infection" (2014). All Theses and Dissertations (ETDs). 1326.