Characterization of the Antiviral Mechanisms of Cyclophilin Inhibitors against Coronavirus Replication
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Authors
Mamatis, John
Date
Type
thesis
Language
eng
Keyword
Antiviral , Broad-spectrum antiviral , Innate immunity , Cyclophilins , Coronavirus , Pandemic preparedness
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Abstract
Coronaviruses (CoVs) are zoonotic positive sense RNA (+ssRNA) viruses with pandemic potential, as evidenced by the recent and ongoing SARS-CoV-2 outbreak, which has posed an incredible global health and socioeconomic burden. Cyclophilin inhibitors (CypI) exert broad-spectrum antiviral activities and are a promising antiviral candidate for future emerging CoVs. While CypI have been shown to restrict CoV replication, the mechanisms underlying the antiviral activity of CypI have yet to be elucidated. In this study, we show that CypI such as the classical CypI cyclosporine A (CsA) and the non-immunosuppressive CypI TMN-355 inhibit infection of endemic human CoVs (HCoVs) HCoV-229E and HCoV-OC43 in A549 lung alveolar epithelial cells. Furthermore, CsA treatment of CoV-infected cells induces expression of antiviral genes, such as MX1. Antagonism of IFN-β by CoV-N proteins was not ameliorated by CsA treatment and activation of canonical interferon (IFN) signalling was not enhanced, suggesting a direct effect of CsA in inducing antiviral gene expression. Consistently, treatment of uninfected A549 cells with CsA induces MX1 expression. Loss of interferon regulatory factor 1 (IRF1) expression reduces CsA antiviral potency, although IRF1 mRNA and protein expression are not robustly impacted by CsA treatment. Further, CsA-mediated induction of antiviral gene expression in HCoV-229E-infected cells is dependent on IRF1 and CypD, but not CypA. . Notably, restriction of HCoV-229E replication by CsA is not affected by inhibition of type I IFN signaling, consistent with an IFN-independent role for IRF1 in inducing ISG expression. Collectively, these findings provide mechanistic insight to contribute to our understanding of the broad-spectrum antiviral activity of CypI. Furthermore, this study identifies previously undescribed mechanisms that act to modulate CsA-mediated enhancement of antiviral gene expression during CoV infection.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.