贝塔冠病毒不同地激活综合应激反应以优化肺部衍生细胞系中的病毒复制
David M Renner1,2, Nicholas A Parenti1,2, Susan R Weiss1,2
1Departments of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 19104-6076.
bioRxiv : the preprint server for biology
|October 10, 2024
概括
像MERS-CoV和HCoV-OC43这样的人类β冠病毒依赖于去酸化eIF2α进行复制,与耐受高水平的SARS-CoV-2不同. 病毒策略的这种差异是开发向治疗的关键.
科学领域:
- 病毒学 病毒学
- 分子生物学分子生物学
- 细胞应激反应的应激反应
背景情况:
- 贝塔冠状病毒,包括MERS-CoV,HCoV-OC43和SARS-CoV-2,对人类健康构成重大威胁.
- 这些病毒与综合应激反应 (ISR) /未折叠蛋白质反应 (UPR) 途径相互作用,特别是与PKR类似的ER激酶 (PERK) 途径.
- PERK途径通过eIF2α的酸化来调节蛋白质合成,影响病毒复制.
研究的目的:
- 研究人类β冠状病毒 (HCoV-OC43,SARS-CoV-2,MERS-CoV) 与PERK通路的差异性相互作用.
- 阐明eIF2α脱化在这些病毒的复制效率中的作用.
- 探索针对泛冠状病毒治疗的PERK途径的治疗潜力.
主要方法:
- 使用了三个人类β冠状病毒:HCoV-OC43,SARS-CoV-2和MERS-CoV.
- 使用eIF2α脱酸化的小分子抑制剂.
- 使用了基因切除 (GADD34淘汰) 和淘汰 (CReP siRNA) 策略.
主要成果:
- 这三种病毒都激活了PERK,但只有SARS-CoV-2在感染期间显示出可检测的p-eIF2α.
- 通过p-eIF2α脱化,MERS-CoV和HCoV-OC43的复制得到了增强.
- HCoV-OC43主要利用CReP进行eIF2α脱,而SARS-CoV-2的复制不受这些干预的影响.
结论:
- eIF2α脱化对MERS-CoV和HCoV-OC43复制至关重要,这表明维持高病毒蛋白质合成的策略.
- SARS-CoV-2 似乎对p-eIF2α水平不敏感,可能会降低酸化的调节,以限制宿主转化.
- 病毒与转化控制机制相互作用的差异凸显了对病毒特异性或量身定制的宿主导治疗方法的需求.
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