TY - JOUR
T1 - SARS-CoV-2 spreads through cell-to-cell transmission
AU - Zeng, Cong
AU - Evans, John P.
AU - King, Tiffany
AU - Zheng, Yi Min
AU - Oltz, Eugene M.
AU - Whelan, Sean P.J.
AU - Saif, Linda J.
AU - Peeples, Mark E.
AU - Liu, Shan Lu
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Gerard Lozanski, Richard Gumina, Eric Freed, David Derse, Marc Johnson, Fang Li, and Ali Ellebedy for provision of sera samples, plasmids, and cells. We also thank the NIH AIDS Reagent Program and BEI Resources for supplying important reagents that made this work possible. This work was supported by a fund provided by an anonymous private donor to The Ohio State University and by NIH Grant U54CA260582; additional support of the S.-L.L. laboratory includes NIH Grants R01 AI112381 and R01 AI150473. M.E.P. and T.K. were supported by NIH Grant U19AI131386-04S1 and by the Nationwide Children’s Hospital COVID-19 Seed Fund. L.J.S. was partially supported by National Institute of Child Health and Human Development Grant R01 HD095881. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.
PY - 2022/1/4
Y1 - 2022/1/4
N2 - 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.
AB - 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.
KW - Cell-to-cell transmission
KW - Cell–cell fusion
KW - Neutralization
KW - SARS-CoV-2
KW - Variants of concern
UR - http://www.scopus.com/inward/record.url?scp=85122659890&partnerID=8YFLogxK
U2 - 10.1073/pnas.2111400119
DO - 10.1073/pnas.2111400119
M3 - Article
C2 - 34937699
AN - SCOPUS:85122659890
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
M1 - e2111400119
ER -