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.

背景：基孔肯雅病毒 (CHIKV) 是一种节肢动物传播的 RNA 病毒，它通过积累未折叠或错误折叠的蛋白质来诱导宿主内质网 (ER) 应激。内质网应激激活未折叠蛋白反应 (UPR) 通路，以实现正确的蛋白质折叠和维持细胞稳态。目前尚无批准的药物或疫苗可用于 CHIKV 治疗，因此需要采取药物对策来预防 CHIKV 感染。

目的：为了寻找基孔肯雅热感染的治疗方法，“穿心莲内酯”是一种具有抗病毒、抗炎和免疫调节作用的植物来源的二萜，用于研究其在基孔肯雅热诱导的未折叠蛋白应激和细胞凋亡中的作用。

方法：在穿心莲内酯和 VER-155008（一种 GRP78 抑制剂）上收集的细胞和上清液在 CHIKV 感染和模拟感染的 THP-1 细胞中进行处理，检测 UPR 通路蛋白的差异表达，包括 GRP78、PERK、EIF-2α、IRE-1α 、XBP-1 和 ATF6。此外，通过免疫印迹法检测炎症小体和凋亡通路蛋白，即 caspase-1、caspase-3 和 PARP，并通过 ELISA 检测细胞因子，即 IL-1β、IL-6 和 IFN-γ。

结果：CHIKV感染的THP-1细胞中的穿心莲内酯处理显着降低了IRE1α和下游剪接XBP1蛋白的表达。此外，穿心莲内酯治疗后，CHIKV 诱导的细胞凋亡和病毒蛋白表达也降低。穿心莲内酯与 VER-155008 的比较分析证实，穿心莲内酯在抑制 CHIKV 诱导的内质网应激方面优于 VER-155008。

结论：因此，该研究证实穿心莲内酯是治疗基孔肯雅热的潜在药物，并抑制 CHIKV 诱导的内质网应激和细胞凋亡。