Significance It is currently unknown if SARS-CoV-2 can spread through cell–cell contacts, and if so, the underlying mechanisms and implications. In this work, we show, by using lentiviral pseudotyped virus, that the spike protein of SARS-CoV-2 mediates the viral cell-to-cell transmission, with an efficiency higher than that of SARS-CoV. We also find that cell–cell fusion contributes to cell-to-cell transmission, yet ACE2 is not absolutely required. While the authentic variants of concern (VOCs) B.1.1.7 (alpha) and B.1.351 (beta) differ in cell-free infectivity from wild type and from each other, these VOCs have similar cell-to-cell transmission capability and exhibit differential sensitivity to neutralization by vaccinee sera. Results from our study will contribute to a better understanding of SARS-CoV-2 spread and pathogenesis. 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.
【저자키워드】 SARS-CoV-2, neutralization, variants of concern, cell-to-cell transmission, cell–cell fusion, 【초록키워드】 Treatment, severe acute respiratory syndrome coronavirus 2, neutralizing antibody, ACE2, coronavirus, Pathogenesis, SARS-CoV, VoC, B.1.351, neutralization, COVID-19 pandemic, spike glycoprotein, Infection, Transmission, severe acute respiratory syndrome Coronavirus, angiotensin-converting enzyme 2, Spike protein, Spread, sensitivity, Viral, Pseudotyped virus, B.1.1.7, sera, VOCs, Alpha, Beta, membrane fusion, respiratory, inhibitor, Critical, wild type, mechanism, convalescent sera, COVID-19 patients, SARS-CoV-2 spike, Angiotensin-converting enzyme, Evidence, angiotensin, Contact, Efficiency, endosomal entry, (alpha, (Beta, acute respiratory syndrome, Implications, acute respiratory syndrome coronavirus, enzyme, cultures, while, transmission of SARS-CoV-2, SARS-CoV spike, viral cell, implication, feature, Cell, vaccinee, ENhance, Result, responsible, required, contribute, the spike protein, reveal, impair, lentiviral, reflects, Significance, 【제목키워드】 Transmission, Spread,