Characterization of the antiviral activity of cyclosporine A against dengue virus

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.

Department dc:contributor.department

Biomedical and Molecular Sciences

Year dc:date.issued

2024

Author dc:creator

• Sangwan, Ujjwal

Advisor dc:contributor.supervisor

• Colpitts, Che

• Antiviral immunity
• Cyclosporine A
• Cyclcophlins
• IRF1
• Host-targeted
• Emerging and Re-emerging viruses

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1974/33225

OAI identifier oai:identifier

oai:queensu.scholaris.ca:1974/33225