Date of Award
Doctor of Philosophy
Influenza virus is a contagious respiratory virus responsible for seasonal epidemics and several catastrophic pandemics in the last century. Its genome is comprised of negative sense, single-stranded RNA and, after entering the cell, it is capable of hijacking the host cellular machinery for reproducing its own genetic material. The activation of cellular defenses against influenza viral infection are triggered upon viral entry and help regulate the course of viral infection. This study focused on the interplay between the influenza A virus and the cellular SUMOylation system during viral infection. The first part of this Dissertation deals with the relevance of NS1 SUMOylation during viral infection. We demonstrate that in studies performed in an animal model, infection with viruses containing a non-SUMOylatable NS1 resulted in increased clinical symptoms, morbidity, and mortality. Furthermore, the inhibition of NS1 SUMOylation enabled viral replication in a broad range of organs and increased pathology of influenza viral infection. Together, these results suggest that NS1 SUMOylation may be a factor contributing to the regulation of viral pathogenicity. The second part of this Dissertation deals with NS1`s role in triggering an increase in cellular SUMOylation. We show that the ability of NS1 to be SUMOylated directly correlates to its ability to trigger a global increase in cellular SUMOylation. Furthermore, we show that infection with vaccinia virus and lymphocyctic choriomeningitis virus are also able to trigger a less dramatic, but still detectable, increase in global cellular SUMOylation. Together, these results suggest that increases in cellular SUMOylation are frequently triggered by viral infection and may be a component of the cellular protective responses against viral infection. The last part of this Dissertation deals with the evaluation of a novel fusion protein capable of specifically increasing the SUMOylation of NS1 (known as NS1(1-87)-Ubc9) as a potential therapeutic agent against influenza viral infection. Our results indicate that the two methods used to deliver the NS1(1-87)-Ubc9 artificial SUMO ligase are effective. Overall, our results suggest that the global increase in cellular SUMOylation, which is associated with NS1 SUMOylation, may constitute a defense mechanism mounted by the host to inhibit the progression of influenza viral infection.
Received from ProQuest
Katherine Anne Meraz
Meraz, Katherine Anne, "Characterization of NS1 SUMOylation and Its Effect on Influenza A Viral Infection" (2014). Open Access Theses & Dissertations. 1299.