Andrographolide Mitigates Unfolded Protein Response Pathway and Apoptosis Involved in Chikungunya Virus Infection

Background: Chikungunya virus (CHIKV) is an arthropod-borne RNA virus which induces host Endoplasmic Reticulum (ER) stress by accumulating unfolded or misfolded proteins. ER stress activates the unfolded protein response (UPR) pathway to enable proper protein folding and maintain cellular homeostasis. There is no approved drug or vaccine available for CHIKV treatment, therefore, a pharmacological countermeasure is warranted for preventing CHIKV infection. Objective: With a view to find a treatment modality for chikungunya infection, “andrographolide”, a plant-derived diterpenoid with reported antiviral, anti-inflammatory and immunomodulatory effects, was used to investigate its role in chikungunya induced unfolded protein stress and apoptosis. Methods: Cells and supernatant collected on andrographolide and VER-155008, a GRP78 inhibitor, treatment in CHIKV infected and mock-infected THP-1 cells were tested for differential expression of UPR pathway proteins including GRP78, PERK, EIF-2α, IRE-1α, XBP-1 and ATF6. Furthermore, the inflammasome and apoptosis pathway proteins, i.e., caspase-1, caspase-3 and PARP, were tested by immunoblotting, and cytokines, i.e., IL-1β, IL-6 and IFN-γ were tested by ELISA. Results: Andrographolide treatment in CHIKV infected THP-1 cells significantly reduced IRE1α and downstream spliced XBP1 protein expression. Furthermore, CHIKV induced apoptosis and viral protein expression were also reduced on andrographolide treatment. A comparative analysis of andrographolide versus VER-155008, confirmed that andrographolide surpasses the effects of VER-155008 in suppressing the CHIKV induced ER stress. Conclusion: The study, therefore, confirms that andrographolide is a potential remedy for chikungunya infection and suppresses CHIKV induced ER stress and apoptosis.