机构：[1]Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.四川大学华西医院[2]National Kunming High-level Biosafety Primate Research Center, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, Yunnan, China.[3]State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.[4]Affiliated Dongguan Hospital, Southern Medical University (Dongguan People's Hospital), Guangzhou, Guangdong, China.[5]Department of Biology and School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong, China.[6]National Clinical Eye Research Center, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.[7]Institute of AI in Medicine and Faculty of Medicine, Macau University of Science and Technology, Taipa, Macau, China.
Soluble host factors in the upper respiratory tract can serve as the first line of defense against SARS-CoV-2 infection. In this study, we described the identification and function of a human airway trypsin-like protease (HAT), capable of reducing the infectivity of ancestral SARS-CoV-2. Further, in mouse models, HAT analogue expression was upregulated by SARS-CoV-2 infection. The antiviral activity of HAT functioned through the cleavage of the SARS-CoV-2 spike glycoprotein at R682. This cleavage resulted in inhibition of the attachment of ancestral spike proteins to host cells, which inhibited the cell-cell membrane fusion process. Importantly, exogenous addition of HAT notably reduced the infectivity of ancestral SARS-CoV-2 in vivo. However, HAT was ineffective against the Delta variant and most circulating Omicron variants, including the BQ.1.1 and XBB.1.5 subvariants. We demonstrate that the P681R mutation in Delta and P681H mutation in the Omicron variants, adjacent to the R682 cleavage site, contributed to HAT resistance. Our study reports what we believe to be a novel soluble defense factor against SARS-CoV-2 and resistance of its actions in the Delta and Omicron variants.
基金：
This work was supported by the National Science Foundation
for Excellent Young Scholars (32122052), and National Natural
Science Foundation Regional Innovation and Development (No.
U19A2003). Figure 4A, Figure 5, I and K and the graphical abstract
were created by BioRender.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2024]版：
无
最新[2023]版：
大类|1 区医学
小类|1 区医学：研究与实验
第一作者：
第一作者机构：[1]Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
共同第一作者：
通讯作者：
通讯机构：[1]Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.[2]National Kunming High-level Biosafety Primate Research Center, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, Yunnan, China.[6]National Clinical Eye Research Center, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.[7]Institute of AI in Medicine and Faculty of Medicine, Macau University of Science and Technology, Taipa, Macau, China.[*1]West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, China[*2]Institute of Medical Biology, Chinese Academy of Medical Sciences, 935 Jiaoling Road, Kunming, Yunnan 650118, China[*3]Eye Hospital, Wenzhou Medical University, 270 West Xueyuan Road, Wenzhou, Zhejiang 325027, China
推荐引用方式(GB/T 7714)：
Ren Wenyan,Hong Weiqi,Yang Jingyun,et al.SARS-CoV-2 Delta and Omicron variants resist spike cleavage by human airway trypsin-like protease[J].The Journal Of Clinical Investigation.2024,134(18):doi:10.1172/JCI174304.
APA：
Ren Wenyan,Hong Weiqi,Yang Jingyun,Zou Jun,Chen Li...&Wei Xiawei.(2024).SARS-CoV-2 Delta and Omicron variants resist spike cleavage by human airway trypsin-like protease.The Journal Of Clinical Investigation,134,(18)
MLA：
Ren Wenyan,et al."SARS-CoV-2 Delta and Omicron variants resist spike cleavage by human airway trypsin-like protease".The Journal Of Clinical Investigation 134..18(2024)
医学