冠状病毒内啡核酶对抗ZBP1介导的亡并延迟多个细胞死亡途径
Monika Evdokimova1, Shuchen Feng1, Allen Caobi2,3
1Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153.
概括
冠状病毒使用nsp15/EndoU来抑制宿主免疫力并延迟细胞死亡. 抑制这种酶会激活免疫传感器,限制病毒传播和疾病.
科学领域:
- 病毒学 病毒学
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- 冠状病毒拥有保存的机制来逃避宿主天生的免疫反应.
- 非结构性蛋白15 (nsp15) 是一种保存的内啡核核酶 (EndoU),对病毒复制和免疫逃避至关重要.
- 准病毒EndoU是一种有前途的抗病毒策略,但活性位点抑制剂的开发具有挑战性.
研究的目的:
- 调查冠状病毒nsp15/EndoU在对抗宿主天生的免疫力中的作用.
- 确定对nsp15/EndoU活动至关重要的保存残留物.
- 确定nsp15/EndoU损失对宿主传感器激活和病毒病原性的影响.
主要方法:
- 为SARS-CoV-2和MHV-A59产生了nsp15突变体.
- 评估了nsp15/EndoU活性,并确定了氨基终端域中的基本残留物.
- 利用转录性分析来分析宿主传感器的激活.
- 评估病毒复制,细胞死亡途径 (死,亡,热),以及体内疾病减弱.
主要成果:
- 在nsp15的氨基末端域中保存的残留物对EndoU活性至关重要.
- 失去nsp15/EndoU活动会触发宿主传感器,包括Z型核酸结合蛋白1 (ZBP1).
- nsp15/EndoU缺乏的病毒会诱导ZBP1介导的亡,ZBP1独立的亡和亡,导致早期细胞死亡和有限的病毒复制.
- 在感染MHV nsp15/EndoU突变的小鼠中,疾病严重程度减弱.
结论:
- nsp15的氨基末端域对其内啡核糖核酶功能至关重要.
- nsp15/EndoU活动对于冠状病毒来说至关重要,以逃避宿主免疫传感器并延迟细胞死亡.
- 破坏nsp15/EndoU功能是开发针对冠状病毒的新型抗病毒疗法的可行策略.
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