Volume 31, No 10, Oct 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 10, October 2021: 1047-1060   |  Open Access

ORIGINAL ARTICLES

Mechanical activation of spike fosters SARS-CoV-2 viral infection

Wei Hu^1,† , Yong Zhang^2,† , Panyu Fei^1,3,† , Tongtong Zhang^1,4,† , Danmei Yao^1,† , Yufei Gao^1,3 , Jia Liu^5,6 , Hui Chen² , Qiao Lu^5,6 , Tenny Mudianto⁵ , Xinrui Zhang¹ , Chuxuan Xiao⁷ , Yang Ye⁸ , Qiming Sun¹ , Jing Zhang⁹ , Qi Xie¹⁰ , Pei-Hui Wang⁹ , Jun Wang^5,6,* , Zhenhai Li^11,* , Jizhong Lou^2,12,13,* , Wei Chen^1,7,14,*

¹Department of Cardiology of the Second Affiliated Hospital and Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
²Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
³School of Mechanical Engineering, Zhejiang University, Hangzhou, Zhejiang, China
⁴Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
⁵Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA
⁶The Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA
⁷Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the MOE Frontier Science Center for Brain Science & Brain-machine Integration, State Key Laboratory for Modern Optical Instrumentation Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, Zhejiang, China
⁸Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, Chin
⁹Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
¹⁰Westlake Institute for Advanced Study, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
¹¹Shanghai Key Laboratory of Mechanics in Energy Engineering, Shanghai Institute of Applied Mathematics and Mechanics, School of Mechanics and Engineering Science, Shanghai University, Shanghai, China
¹²University of Chinese Academy of Sciences, Beijing, China
¹³Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong, China
¹⁴Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
^†These authors contributed equally: Wei Hu, Yong Zhang, Panyu Fei, Tongtong Zhang, Danmei Yao
Correspondence: Jun Wang(jun.wang@nyulangone.org)Zhenhai Li(lizhshu@shu.edu.cn)Jizhong Lou(jlou@ibp.ac.cn)Wei Chen(jackweichen@zju.edu.cn)

The outbreak of SARS-CoV-2 (SARS2) has caused a global COVID-19 pandemic. The spike protein of SARS2 (SARS2-S) recognizes host receptors, including ACE2, to initiate viral entry in a complex biomechanical environment. Here, we reveal that tensile force, generated by bending of the host cell membrane, strengthens spike recognition of ACE2 and accelerates the detachment of spike’s S1 subunit from the S2 subunit to rapidly prime the viral fusion machinery. Mechanistically, such mechano-activation is fulfilled by force-induced opening and rotation of spike’s receptor-binding domain to prolong the bond lifetime of spike/ACE2 binding, up to 4 times longer than that of SARS-S binding with ACE2 under 10 pN force application, and subsequently by force-accelerated S1/S2 detachment which is up to ~103 times faster than that in the no-force condition. Interestingly, the SARS2-S D614G mutant, a more infectious variant, shows 3-time stronger force-dependent ACE2 binding and 35-time faster force-induced S1/S2 detachment. We also reveal that an anti-S1/S2 non-RBD-blocking antibody that was derived from convalescent COVID-19 patients with potent neutralizing capability can reduce S1/S2 detachment by 3 × 106 times under force. Our study sheds light on the mechano-chemistry of spike activation and on developing a non-RBD-blocking but S1/S2-locking therapeutic strategy to prevent SARS2 invasion.

https://doi.org/10.1038/s41422-021-00558-x

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