亚洲糖蛋白受体1促进了SARS-CoV-2感染人类正常肝细胞的发生
Xinyi Yang1, Xu Zheng2, Yuqi Zhu1
1State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China.
Signal transduction and targeted therapy
|February 14, 2024
概括
亚洲糖蛋白受体1 (ASGR1) 促进SARS-CoV-2进入肝细胞,独立于ACE2. 抑制ASGR1显著减少肝细胞中的病毒感染,确定它是SARS-CoV-2的关键入口受体.
科学领域:
- 肝病学 肝病学是一种肝病学.
- 病毒学 病毒学
- 分子生物学分子生物学
背景情况:
- 严重急性呼吸道综合征冠状病毒2 (SARS-CoV-2) 导致多器官损伤,包括超过50%的患者肝功能障碍.
- ангиотензин I转化酶2 (ACE2) 是主要的SARS-CoV-2受体,但其在肝细胞中的低表达表明了其他进入途径.
研究的目的:
- 为了研究SARS-CoV-2进入ACE2之外的肝细胞的替代受体.
- 确定和描述亚洲糖蛋白受体1 (ASGR1) 在SARS-CoV-2感染肝细胞中的作用.
主要方法:
- 全基因组的CRISPR-Cas9激活查以确定宿主因素.
- 在各种细胞系 (HeLa, Huh-7, THLE-2) 和初级肝细胞中测试SARS-CoV-2伪病毒和活病毒感染.
- 进行ASGR1淘汰,抗体中和和siRNA抑制实验.
- 使用受体结合域 (RBD) 和N端域 (NTD) 的尖端蛋白相互作用研究.
- 免疫组织化学和电子显微镜以确认病毒感染和局部化.
主要成果:
- 全基因组查发现ASGR1是SARS-CoV-2伪病毒感染的促进者.
- 同时淘汰ACE2和ASGR1阻止了Huh-7细胞中的伪病毒感染.
- 抑制ASGR1 (抗体或siRNA) 显著降低了SARS-CoV-2伪病毒和低ACE2表达的肝细胞中的活病毒感染.
- ASGR1与SARS-CoV-2尖端蛋白相互作用,特别是通过其RBD和NTD.
- 在ASGR1抑制后,初级肝细胞的SARS-CoV-2感染得到证实并显著减少.
结论:
- ASGR1是SARS-CoV-2进入肝脏辅酶细胞的关键受体,其功能独立于ACE2.
- ASGR1代表了减轻SARS-CoV-2引起的肝损伤的潜在治疗标.
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