SARS-CoV-2 Delta and Omicron variants resist spike cleavage by human airway trypsin-like protease
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.
Authors
- Xiawei Wei (ORCID: https://orcid.org/0000-0002-6513-6422)
- Wenyan Ren (ORCID: https://orcid.org/0000-0001-6333-8496)
- Yanan Zhou (ORCID: https://orcid.org/0000-0003-2225-3001)
- Wei Cheng (ORCID: https://orcid.org/0000-0002-7820-9774)
- Weiqi Hong (ORCID: https://orcid.org/0000-0003-1668-2301)
- Xikun Zhou (ORCID: https://orcid.org/0000-0001-6768-2382)
- Jingmei Li (ORCID: https://orcid.org/0000-0001-8587-7511)
- Aqu Alu (ORCID: https://orcid.org/0000-0002-9981-0120)
- Xuelei Ma (ORCID: https://orcid.org/0000-0002-9148-5001)
- Zhenfei Bi (ORCID: https://orcid.org/0000-0001-6467-8484)
- Yanqiu Gong (ORCID: https://orcid.org/0000-0001-7890-5158)
- Minyang Fu
- Haiying Que (ORCID: https://orcid.org/0000-0002-3994-8857)
- Qing Huang (ORCID: https://orcid.org/0000-0002-2008-9888)
- Guobo Shen (ORCID: https://orcid.org/0000-0002-8917-196X)
- Haohao Dong (ORCID: https://orcid.org/0000-0002-5022-3494)
- Mengli Yang (ORCID: https://orcid.org/0000-0001-5108-648X)
- Hanpei Miao (ORCID: https://orcid.org/0000-0002-0166-0866)
- Guowen Jia (ORCID: https://orcid.org/0000-0002-6507-6204)
- Jun Zou (ORCID: https://orcid.org/0000-0002-5395-6052)
- Guangwen Lu (ORCID: https://orcid.org/0000-0001-7568-592X)
- Jian Lei (ORCID: https://orcid.org/0000-0001-9326-0554)
- Bin Shao
- Dandan Peng (ORCID: https://orcid.org/0000-0003-1212-7917)
- Hongbo Hu (ORCID: https://orcid.org/0000-0002-8177-7641)
- Shuaiyao Lu (ORCID: https://orcid.org/0000-0003-1675-9735)
- Lunzhi Dai (ORCID: https://orcid.org/0000-0002-3003-8910)
- Zhaoming Su (ORCID: https://orcid.org/0000-0002-9279-1721)
- Yuquan Wei (ORCID: https://orcid.org/0000-0002-6211-3217)
- Wenhai Yu (ORCID: https://orcid.org/0000-0002-3205-2062)
- H. J. Yang (ORCID: https://orcid.org/0009-0004-8274-9863)
- Li Chen (ORCID: https://orcid.org/0000-0002-9650-497X)
- Wei Wang (ORCID: https://orcid.org/0000-0001-7788-1895)
- Yang Li (ORCID: https://orcid.org/0000-0002-6515-4567)
- Lu Chen (ORCID: https://orcid.org/0000-0002-1083-9729)
- Kang Zhang (ORCID: https://orcid.org/0000-0002-4549-1697)
- Bai Li (ORCID: https://orcid.org/0000-0003-1311-9206)
- Jiong Li
- Yun Yang (ORCID: https://orcid.org/0000-0002-9986-5930)
- Zhenling Wang (ORCID: https://orcid.org/0000-0003-0364-8948)
- Junbin Wang (ORCID: https://orcid.org/0000-0002-9668-0666)
- Cong Tang (ORCID: https://orcid.org/0000-0003-2718-2820)
- Cai He (ORCID: https://orcid.org/0000-0002-9959-1562)
- Jinliang Yang
- Johnson Yiu‐Nam Lau
- Lei Hong (ORCID: https://orcid.org/0000-0002-3813-7112)
Institutions
- Macau University of Science and Technology (MO)
- Hong Kong Baptist University (HK)
- Kunming Institute of Zoology (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Sichuan University (CN)
- Wenzhou Medical University (CN)
- Affiliated Eye Hospital of Wenzhou Medical College (CN)
- Dongguan People’s Hospital (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1172/jci174304
- Citations
- 3
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- National Science Foundation