Antiviral and immunomodulatory effect of Curcumin and its analogues on influenza virus and Rhinovirus infections

Infections by respiratory viruses such as influenza A virus (IAV) and rhinovirus (RV) frequently trigger exacerbations of chronic respiratory diseases due to virus-induced airway inflammatory responses. The lack of antiviral drugs, antiviral resistance and suppression of antiviral immunity by corticosteroids for chronic respiratory diseases warrant a search of new therapeutic agents. Curcumin has shown anti-inflammatory as well as antiviral effects against several viruses including IAV; however, poor bioavailability hinders its development. Curcumin-like diarylpentanoid analogues, namely 2-benzoyl-6- (3,4-dihydroxybenzylidene)cyclohexen-1-ol (BDHBC) and 5-(3,4- dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DHHPD), have shown better anti-inflammatory effects, solubility and stability compared to curcumin. Therefore, this study aims to evaluate the in vitro inhibitory effects of curcumin and its analogues (BDHBC and DHHPD) on IAV and RV infections and their induced cytokine responses. The non-cytotoxic concentrations of curcumin, BDHBC and DHHPD were determined via MTT assay. Their antiviral effects for IAV (A/Puerto Rico/8/34) and RV (RV-16) were assessed in A549 and H1 HeLa cells, respectively, using cytopathic effect (CPE) reduction assay, virus yield reduction assay, RT-qPCR, immunofluorescence, and Western blot. Time-of-addition analysis was also carried out to identify the best mode of antiviral treatment. ELISA and RT-qPCR were used to examine the effects of curcumin, BDHBC and DHHPD on IAV- or RV-induced pro￾inflammatory cytokines and interferons production in airway epithelial cell lines (A549 and BEAS-2B). To explore the potential mechanisms of action, Western blot was used to identify the signalling pathways inhibited by curcumin, BDHBC and DHHPD. Treatment of IAV-infected A549 cells with curcumin, BDHBC and DHHPD significantly attenuated (p < 0.001) IAV replication by reducing progeny virus release and viral nucleoprotein (NP) expression at both gene and protein levels. Additionally, DHHPD, but not curcumin and BDHBC, demonstrated significant prophylactic antiviral effects against IAV (p < 0.05). All three compounds also have virucidal effect on IAV (curcumin: p < 0.001; BDHBC and DHHPD: p < 0.01). Besides that, curcumin, BDHBC and DHHPD also significantly suppressed (p < 0.001) IAV-induced pro-inflammatory cytokines (IL- 6, IL-8 and IP-10) and interferons (IFN-β and IFN-λ1) expression at both gene and protein levels. Curcumin and DHHPD were found to inhibit multiple signalling pathways mediated by retinoic acid-inducible gene-I (RIG-I), including NF-κB, AP-1, MAPKs (p38 and Erk1/2), IRF3 and Akt, without modulating the expression of RIG-I. Overall, the strongest inhibitory effect against IAV infection and cytokine responses was shown by curcumin, followed by DHHPD and BDHBC. By contrast, BDHBC demonstrated the strongest antiviral effect against RV infection in H1 HeLa cells, followed by DHHPD and curcumin. Curcumin, BDHBC and DHHPD treatment significantly attenuated (p < 0.001) CPE, progeny virus release, vRNA and viral proteins (P1, VP0 and VP2) expression in RV-infected H1 HeLa cells. Furthermore, BDHBC demonstrated prophylactic antiviral effect by reducing basal expression of ICAM-1 (p < 0.05) as well as virucidal effect (p < 0.05) against RV-16. However, as cytotoxicity restricted the use of similar concentrations as in H1 HeLa cells, curcumin, BDHBC and DHHPD had no effect on the secretion of pro-inflammatory cytokines (IL-6 and IL-8) in RV-infected BEAS-2B cells. In conclusion, curcumin and its analogues (BDHBC and DHHPD) have significant antiviral and/or anti-inflammatory effects during IAV and RV infections. Their potential therapeutic effects should be further explored in vivo using animal infection models.

Text FPSK (p) 2023 19 - Declaration Form.pdf Restricted to Repository staff only Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (611kB) Text FPSK (p) 2023 19 - Full Text.pdf Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (10MB) Text FPSK (p) 2023 19.pdf Restricted to Repository staff only Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (10MB)

Actions (login required)

View Item