Panny Lauren, Akrhymuk Ivan, Bracci Nicole, Woodson Caitlin, Flor Rafaela, Elliott Isaac, Zhou Weidong, Narayanan Aarthi, Campbell Catherine, Kehn-Hall Kylene
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24060, USA; Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24060, USA.
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24060, USA.
Antiviral Res. 2023 Apr;212:105560. doi: 10.1016/j.antiviral.2023.105560. Epub 2023 Feb 22.
Venezuelan equine encephalitis virus (VEEV) is an alphavirus transmitted by mosquitos that can cause a febrile illness and induce severe neurological complications in humans and equine populations. Currently there are no FDA approved vaccines or antiviral treatments to combat VEEV. Proteomic techniques were utilized to create an interactome of the E1 fusion glycoprotein of VEEV. VEEV E1 interacted with a number of cellular chaperone proteins including protein disulfide isomerase family A member 6 (PDIA6). PDI inhibition through LOC14 and/or nitazoxanide treatment effectively decreased production of VEEV and other alphaviruses in vitro, including eastern equine encephalitis virus, Sindbis virus, and chikungunya virus. Decreased oxidoreductive capabilities of PDIs through LOC14 or nitazoxanide treatment impacted both early and late events in viral replication, including the production of non-infectious virions and decreased VEEV E1 disulfide bond formation. Results from this study identified PDIs as critical regulators of alphavirus replication and potential therapeutic targets.
委内瑞拉马脑炎病毒（VEEV）是一种由蚊子传播的甲病毒，可导致发热性疾病，并在人类和马群中引发严重的神经并发症。目前，美国食品药品监督管理局（FDA）尚未批准用于对抗VEEV的疫苗或抗病毒治疗方法。蛋白质组学技术被用于构建VEEV E1融合糖蛋白的相互作用组。VEEV E1与多种细胞伴侣蛋白相互作用，包括蛋白质二硫键异构酶A家族成员6（PDIA6）。通过LOC14和/或硝唑尼特处理抑制PDI，可有效降低体外VEEV和其他甲病毒的产生，包括东部马脑炎病毒、辛德毕斯病毒和基孔肯雅病毒。通过LOC14或硝唑尼特处理降低PDI的氧化还原能力，会影响病毒复制的早期和晚期事件，包括非感染性病毒粒子的产生以及VEEV E1二硫键形成的减少。本研究结果确定PDI是甲病毒复制的关键调节因子和潜在的治疗靶点。
