Examination of type I IFN mediated regulation of the post-transcriptional antiviral response
type: CreativeWork
description: 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 produc…
abstract: 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 produc…
author: Burke, James Daniel
keywords: antiviral, innate immune response, interferon, metabolism, translation, virus
date published: 2015
date modified: 2026-07-27T21:28:22Z
provider: University of Toronto
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Toronto

PropertyValue
property ID: Handle
value: http://hdl.handle.net/1807/79723