Characterization of the antiviral activity of cyclosporine A against dengue virus
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Authors
Sangwan, Ujjwal
Date
2024-07-31
Type
thesis
Language
eng
Keyword
Antiviral immunity , Cyclosporine A , Cyclcophlins , IRF1 , Host-targeted , Emerging and Re-emerging viruses
Alternative Title
Abstract
Dengue virus (DENV) currently threatens 3.9 billion people, a number expected to rise to 6.1
billion by 2080, yet no specific antiviral treatments are available despite 80 years of research.
Cyclosporine A (CsA), an immunosuppressive drug, has emerged as a potential broad-spectrum
antiviral effective against various RNA and DNA viruses, including DENV. However, its antiviral
mechanism is not fully understood, and its effectiveness against DENV-2 in different cell lines has
yet to be explored. In this study, we evaluated the antiviral activity and mechanism of CsA against
DENV-2 in A549 lung alveolar epithelial cells, Huh7 human hepatoma cells, and THP-1
monocyte-derived macrophages. We demonstrated that CsA effectively inhibits DENV-2 in all
three cell types. Notably, the antiviral activity of CsA against DENV-2 is independent of its target
proteins, cyclophilin A or B, which are not required host factors for DENV-2 in Huh7 and A549
cells. In Huh7 and A549 cells, CsA induces interferon regulatory factor-1 (IRF1)-dependent
antiviral gene expression. While CsA does not increase IRF1 levels in Huh7 cells, it enhances
IRF1 protein levels in A549 cells, which may contribute to its inhibitory effect against DENV-2.
CsA inhibits cyclophilins, whose chaperone function likely contributes to proteostasis, leading to
endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). The
UPR is closely linked with several major signalling pathways and can induce IRF1 expression.
Evidence suggests that CsA-induced ER stress inhibits viral infection. We discovered that in A549
cells, CsA treatment induces ER-stress associated genes as well as MX1 in DENV-2 infected cells,
and the induction of ER stress results in the inhibition of DENV-2. Overall, our findings suggest
that CsA induces ER stress, leading to the induction of MX1 via IRF1 and inhibiting DENV-2
infection in A549 cells.
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Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
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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.
Attribution-NonCommercial-NoDerivatives 4.0 International
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.
Attribution-NonCommercial-NoDerivatives 4.0 International