2. Academic Validation
  3. Antibody-mediated spike activation promotes cell-cell transmission of SARS-CoV-2

Antibody-mediated spike activation promotes cell-cell transmission of SARS-CoV-2

  • PLoS Pathog. 2023 Nov 10;19(11):e1011789. doi: 10.1371/journal.ppat.1011789.
Shi Yu 1,  Xu Zheng 1,  Yanqiu Zhou 2,  Yuhui Gao 1,  Bingjie Zhou 1,  Yapei Zhao 1,  Tingting Li 3,  Yunyi Li 2,  Jiabin Mou 2,  Xiaoxian Cui 2,  Yuying Yang 2,  Dianfan Li 3,  Min Chen 2,  Dimitri Lavillette 1 4 5,  Guangxun Meng 1 4 6
Affiliations

Affiliations

  • 1 The Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology & Immunology, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Shanghai, China.
  • 2 Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
  • 3 State Key Laboratory of Molecular Biology, State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (CAS), Shanghai, China.
  • 4 Pasteurien College, Soochow University, Suzhou, Jiangsu, China.
  • 5 Applied Molecular Virology Laboratory, Discovery Biology Department, Institut Pasteur Korea, Gyeonggi-do, South Korea.
  • 6 Nanjing Advanced Academy of Life and Health, Nanjing, Jiangsu, China.
PMID: 37948454 DOI: 10.1371/journal.ppat.1011789
Abstract

The COVID pandemic fueled by emerging SARS-CoV-2 new variants of concern remains a major global health concern, and the constantly emerging mutations present challenges to current therapeutics. The spike glycoprotein is not only essential for the initial viral entry, but is also responsible for the transmission of SARS-CoV-2 components via syncytia formation. Spike-mediated cell-cell transmission is strongly resistant to extracellular therapeutic and convalescent Antibodies via an unknown mechanism. Here, we describe the antibody-mediated spike activation and syncytia formation on cells displaying the viral spike. We found that soluble Antibodies against receptor binding motif (RBM) are capable of inducing the proteolytic processing of spike at both the S1/S2 and S2' cleavage sites, hence triggering ACE2-independent cell-cell fusion. Mechanistically, antibody-induced cell-cell fusion requires the shedding of S1 and exposure of the fusion peptide at the cell surface. By inhibiting S1/S2 proteolysis, we demonstrated that cell-cell fusion mediated by spike can be re-sensitized towards antibody neutralization in vitro. Lastly, we showed that cytopathic effect mediated by authentic SARS-CoV-2 Infection remain unaffected by the addition of extracellular neutralization Antibodies. Hence, these results unveil a novel mode of antibody evasion and provide insights for antibody selection and drug design strategies targeting the SARS-CoV-2 infected cells.

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