SARS-CoV-2 spreads through cell-to-cell transmission

Cong Zeng, John P. Evans, Tiffany King, Yi Min Zheng, Eugene M. Oltz, Sean P.J. Whelan, Linda J. Saif, Mark E. Peeples, Shan Lu Liu

Research output: Contribution to journalArticlepeer-review

81 Scopus citations


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein, we provide evidence that SARS-CoV-2 spreads through cell–cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than is SARS-CoV spike, which reflects, in part, their differential cell–cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While angiotensin-converting enzyme 2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the authentic variants of concern (VOCs) B.1.1.7 (alpha) and B.1.351 (beta) have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccinee sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis.

Original languageEnglish
Article numbere2111400119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number1
StatePublished - Jan 4 2022


  • Cell-to-cell transmission
  • Cell–cell fusion
  • Neutralization
  • SARS-CoV-2
  • Variants of concern


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