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Examination of Type I IFN Mediated Regulation of the Post-Transcriptional Antiviral Response

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Examination of Type I IFN Mediated Regulation of the Post-Transcriptional Antiviral Response Examination of type I IFN mediated regulation of the post-transcriptional antiviral response by J. Daniel Burke A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Immunology University of Toronto © Copyright by J Daniel Burke (2015) Examination of type I IFN mediated regulation of the post-transcriptional antiviral response. Doctor of Philosophy Department of Immunology University of Toronto 2015 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 produced a significant antiviral effect during the acute phase of viral myocarditis caused By Coxsackievirus B3 infection. ii 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. iii Acknowledgements Thank you. I am indeBted to so many who have helped me climb this mountain. When hiking a mountain, not every step is predictaBle, and often there are slips and falls. You have Been there to keep me on the path, and help me up along the way. Firstly, Eleanor, you have Been immensely supportive over the years! Thank you for your steadfast guidance and aBundant patience. You know that this has not Been a path easily navigated, But you have seen me through to the end. Your kindness and generosity have Been hallmarks of the laB, and I will never forget the confidence that you invested in your trainees. I look forward to the years to come, and will take with me your ‘can-do’ attitude, and perseverence. Thank you for Being my mentor! Dana and Gary, I thank you Both for your support through my degree. I recognize that you Both have such Busy schedules. You have so kindly taken time to hear updates aBout my project and provide helpful feedBack. Thank you especially in this last stage of my program for reviewing my thesis! I have heard people say that PhD stands for “permanent head damage”. There is more than a grain of truth to this. In and around the laB many of you have kept this effect to a minimum By diluting the tedium of cell splitting and virus titrations with laughter and levity. Ramtin, you were an incrediBle multi-dimensional encouragement all through my degree. From the pre-interview that I had with you Before ever meeting Eleanor, all the way to my defense you had my Back. Thomas, you were an excellent scientific role model! I thank you for Bringing your fastidious attention to experimental detail to the laB. Such a high Benchmark that you’ve set! Jae, I will never forget the degree to which you persevered and worked to get those papers out. I hope to emulate the fervour with which you approached your science. Carole, you were an everflowing fount of knowledge in both technical and general principles alike. Thank you for initiating so many lunchroom scientific discourses. I will miss your “ridiculous” questions! Beata, you are a cornerstone of the laB. Beyond keeping everything running so smoothly, your positive outlook was continually a source of reassurance that the sky would not fall. Danlin, thank you for the energy and laughter that you added during your time here. You kept me on my toes. I’m still “thinking aBout it”. Olivia, thank you for your cheerful presence all along the way, even after migrating across University Ave. The word metaBolism has Been given new meaning because of discussions with you. Ben, I have appreciated your enormously helpful and diligent character. Thank you for Being the pillar that you are in the Fish laB! Leesa, your meticulous conduct and hard work in the laB has Been a real inspiration to me. May your antibodies always be bright! Craig, thank you for keeping me company By the spec. Whether you knew it or not, you often added a much needed perspective when I was Buried in 100s of mouse tissues. Darrin, I am really excited to see you move forward with the metaBolism work. I can’t wait to see it on PuBmed! Erin, you added a healthy dose of vitality to the laB. I hope that ps20 did not do any irreversiBle damage, and that you go to help solve real proBlems in the medical world of Toronto! iv There are so many in the research community that I have failed to mention, but have contriButed to making this journey just that little Bit smoother. I think of the many individuals in support-staff roles that are never included on papers. They are owed a great debt of gratitude as well. Thank you for your service! To my dear friends at Grace Toronto, you were an integral thread to my life in Toronto! You challenged me in real ways, and were such a tangiBle representation of what the ‘Body of Christ’ is as a community. It is so exciting to see the impact that Grace is having in reaching the hidden, and not so hidden, brokeness of this great city. Mom and Dad, you have Been unspeakaBle supports to me in my academic pursuit! My DNA is from you, and you have given me this curiousity to pursue science. Through all the rapids and calm water you have Been with me in the canoe. Thank you for the ceaseless prayer that you offered on my Behalf. I am incrediBly fortunate to have supportive parents like you! Andrea, I’m not sure who convinced who to get into Immunology, But now it seems that we’re both branded with this super-cool field of medicine. Thank you for the natural aBility that you Bring to facilitating community and relationships. Both you and Meg found Jenny! Thanks! Meg, it’s Been fun to tag along with you periodically to meet your uBer-hip architecture friends. I’m certain that God has you in this sphere for a particular reason, and that you are impacting those around you in ways that you do not know. Joe, you’re a great brother! You are such a positive and helpful person to be around. You add such a “spark” whereever you go. I think that you should come with a warning laBel. Aaron, you’re now a new Brother, and a Brave one at that. I’m looking forward to the future adventures that we will experience together. To my new friends in the West, I thank you. Since Before Jenny and I were married, you have supported us. I am so thankful for the many practical ways that you have done this. In addition, I deeply appreciate that you continually pray for one another, and that we have been recipients of this real aspect of Christian life. Larry and Connie, thank you for the kindness that you have shown toward me as I learn the ropes of marriage. I am so thankful for your support, and that you pray for us so diligently. I look forward to the craZy family adventures that lie ahead of us. Even now, I am sitting on a beach in Nassau writing this as you float down a lazy river. Thank you! Jenny, you have Been my partner in this last leg of the journey. I have so much to Be thankful for in having you By my side! You are a wonderful woman! Your steady encouragement and confidence in me have Been crucial in getting me to the finish line. And your continual prayer has undouBtedly Been instrumental in getting me past so many hurdles. Thank you. I am excited to see where God leads us in the coming years as He continues to unfold His plan for our family! It feels as though I have reached the summit of a significant mountain on this journey.
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