Examining the Role of STATs and STAT Signaling the Induction, Enhancement, and Prolonged Duration of Antiviral Activity by IFN-γ and IFN-α2a in Combination with Ribavirin
Morrow, Angel N.
Interferons (IFNs) were discovered in 1957, yet there are still questions as to how IFNs elicit their antiviral, antiproliferative, and immunomodulatory activities. In addition, IFN-α is part of the standard treatment for Hepatitis C Virus (HCV) in combination with ribavirin (RBV), yet there remain questions as to the mechanism of RBV's antiviral activity and how IFN-α and RBV work together to clear viral infections. Since these treatments result in serious side effects, I aim to understand their mechanisms of action in order to ascertain new ways to specifically inducing antiviral activity. In this dissertation, I examine multiple components that contribute to prolonging and enhancing the antiviral response of IFN-γ, and IFN-α in combination with RBV. First, I identified a novel transcription factor, ISGF3II, which is induced by prolonged IFN-γ treatment and contains phosphorylated STAT1, unphosphorylated STAT2, and IRF9. ISGF3II demonstrates the role of unphosphorylated STATs in prolonging the induction of IFN-stimulated genes (ISGs) characteristically involved in antiviral activity. Further, I show that the components of ISGF3 can form in the absence of IFN treatment, suggesting that antiviral activity may be induced in the absence of IFN. I also show that low doses of IFN-α and RBV in combination are capable of inducing enhanced and prolonged phosphorylation of both STAT1 and STAT2. The increased duration of STAT signaling coincides with enhanced and prolonged induction of ISGs. Furthermore, I show that RBV is capable of binding to and inhibiting the activity of several cytoskeletal GTPases, including CDC42 and RhoA. RBV also inhibits the formation of microtubules through inhibition of tubulin polymerization. In vitro assays show that RBV treatment inhibits invasion of a adenocarcinomic alveolar epithelial cell through a permeable membrane, and that it also prevents trafficking of the Vesicular Stomatitis Virus (VSV) glycoprotein (VSV-G) from its site of replication in the ER-Golgi Intermediate Compartment (ERGIC) to the plasma membrane. Together, these results provide insight as to how the antiviral activity of IFNs can be induced, enhanced, and prolonged. Furthermore, the novel mechanism of RBV action suggests that its clinical applications may extend beyond its sole use as an antiviral drug.
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