Examination of type I IFN mediated regulation of the post-transcriptional antiviral response
Interferons (IFNs) are pleiotropic cytokines that regulate both innate and adaptive immunity. Early post viral infection, there is induction and secretion of IFN-β which alerts nearby cells and primes leukocytes for an immune response. A rapid response is necessary for effective control of virus replication and spread. Previously in our lab, the IFN-α/β inducible PI-3'K/mTOR mediated induction of translation was shown to operate in concert with the prototypical JAK/STAT mediated transcription of IFN stimulated genes (ISGs). In the absence of key signaling intermediates of the PI-3'K/mTOR pathway, namely, Akt or PI-3'K, an IFN-α/β inducible antiviral response was abolished. Given the apparent importance of this pathway, we sought to enhance IFN-α/β signaling by targeting key negative regulatory intermediates. In vitro experiments demonstrated that cells lacking suppressors of translation, TSC2 or 4E-BP1, are more sensitive to IFN-α/β inducible effects as indicated by increased antiviral protein synthesis, and enhanced resistance to virus infection. In vivo experiments showed that mice lacking 4E-BP1 are similarly more resistant to virus infection, and also more sensitive to the antiviral effects of IFN-β treatment. These in vitro and in vivo effects were demonstrated for different viruses, including Vaccinia virus, Influenza virus and Coxsackievirus. Given these findings of rapid mRNA translation to enable a robust IFN antiviral response, and aware that this is an ATP consuming process, we next examined whether IFN-α/β treatment also exerted effects on cell metabolism. Through a series of in vitro experiments we demonstrated rapid IFN-α/β-mediated regulation of glucose uptake in an Akt and PI-3'K dependent manner. Given the number of signaling intermediates shared by IFN-α/β and insulin, we examined the in vivo effects of metformin, an insulin sensitizer, during antiviral treatment with IFN-β. Interestingly, prophylactic treatment with both metformin and IFN-β produced a significant antiviral effect during the acute phase of viral myocarditis caused by Coxsackievirus B3 infection. Taken altogether, the work described in this thesis provides further evidence for the importance of post-transcriptional regulation exerted by IFN-α/β during a virus infection.
antiviral, innate immune response, interferon, metabolism, translation, virus
Networked Digital Library of Theses and Dissertations