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The Role of Type I Interferon Alpha/Beta Receptor Signaling and Sex in Cytokine Responses to Viral Infection

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Title: The Role of Type I Interferon Alpha/Beta Receptor Signaling and Sex in Cytokine Responses to Viral Infection
Author: Darzianiazizi, Maedeh
Department: Department of Pathobiology
Program: Pathobiology
Advisor: Bridle, ByramKarimi, Khalil
Abstract: Viruses are one of the main causes of morbidities and mortalities in humans. However, the outcome of a viral infection can be different between individuals and the cellular and molecular mechanisms underlying the discrepancy in the outcome of a viral infection are not well-understood. Host innate antiviral responses are largely controlled by type I interferons (IFNs) signaling through their specific receptor, type I IFN α/β Receptor (IFNAR). Virus-induced aberrant IFNAR signaling has been shown to be associated with excessive inflammatory responses. Moreover, sex, as an intrinsic factor, has been implicated in differential host predisposition to severe viral infection. In this study, IFNAR-mediated antiviral cytokine responses of male andfemale mice were characterized during viremia of recombinant strain of vesicular stomatitis virus (rVSVΔm51). Our findings highlighted a crucial role for IFNAR signaling in the negative regulation of plasma and hepatic antiviral cytokine responses that could be influenced by sex while IFNAR signaling was disrupted or absent. Further, hepatic IFNAR-mediated antiviral cytokine responses were shown to be influenced by sex which contributed to differential liver damage strongly biased against females. Our in-vitro studies on mouse bone marrow-derived mast cells (BMMCs) infected with rVSVΔm51-infected, implicated mast cells as potential source of exaggerated cytokine responses to rVSVΔm51 when IFNAR-mediated signaling is impaired or absent. We showed that mice BMMCs are infected by VSV and produce pro-inflammatory cytokines in response to rVSVΔM51 infection and that IFNAR signaling is required to shut these responses down and protect the cells from virus-induced death. These findings highlight: 1) a crucial role for IFNAR signaling in negative regulation of systemic and local anti-viral cytokine responses which can be influenced by sex during viremia associated with the lack of IFNAR signaling. 2) A sexually dimorphic landscape of IFNAR-mediated antiviral responses which can make the host either susceptible or resistant to immune-mediated pathogenesis during viremia associated with the lack of IFNAR signaling. 3) Further understanding of sex-mediated antiviral pathways can lead to development of novel, sex-tailored anti-inflammatory therapeutics. 4) Mast cells might represent a therapeutic target to limit excessive anti-viral inflammatory responses resulted from disrupted IFNAR signaling, particularly in females.
URI: http://hdl.handle.net/10214/17762
Date: 2020-01
Rights: Attribution-NonCommercial-NoDerivatives 4.0 International
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Attribution-NonCommercial-NoDerivatives 4.0 International Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International