Cell entry mechanisms of SARS-CoV-2
By J. Shang, Yushun Wan, C. Luo, G. Ye, Q. Geng, Ashley A. Auerbach, Fang Li. Proceedings of the National Academy of Sciences of the United States of America, 2020
2,881 citations recorded by the source corpus.
Significance A key to curbing SARS-CoV-2 is to understand how it enters cells. SARS-CoV-2 and SARS-CoV both use human ACE2 as entry receptor and human proteases as entry activators. Using biochemical and pseudovirus entry assays and SARS-CoV as a comparison, we have identified key cell entry mechanisms of SARS-CoV-2 that potentially contribute to the immune evasion, cell infectivity, and wide spread of the virus. This study also clarifies conflicting reports from recent studies on cell entry of SARS-CoV-2. Finally, by highlighting the potency and the evasiveness of SARS-CoV-2, the study provides insight into intervention strategies that target its cell entry mechanisms. A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) is causing the global coronavirus disease 2019 (COVID-19) pandemic. Understanding how SARS-CoV-2 enters human cells is a high priority for deciphering its mystery and curbing its spread. A virus surface spike protein mediates SARS-CoV-2 entry into cells. To fulfill its function, SARS-CoV-2 spike binds to its receptor human ACE2 (hACE2) through its receptor-binding domain (RBD) and is proteolytically activated by human proteases. Here we investigated receptor binding and protease activation of SARS-CoV-2 spike using biochemical and pseudovirus entry assays. Our findings have identified key cell entry mechanisms of SARS-CoV-2. First, SARS-CoV-2 RBD has higher hACE2 binding affinity than SARS-CoV RBD, supporting efficient cell entry. Second, paradoxically, the hACE2 binding affinity of the entire SARS-CoV-2 spike is comparable to or lower than that of SARS-CoV spike, suggesting that SARS-CoV-2 RBD, albeit more potent, is less exposed than SARS-CoV RBD. Third, unlike SARS-CoV, cell entry of SARS-CoV-2 is preactivated by proprotein convertase furin, reducing its dependence on target cell proteases for entry. The high hACE2 binding affinity of the RBD, furin preactivation of the spike, and hidden RBD in the spike potentially allow SARS-CoV-2 to maintain efficient cell entry while evading immune surveillance. These features may contribute to the wide spread of the virus. Successful intervention strategies must target both the potency of SARS-CoV-2 and its evasiveness.
Subfields: Infectious Diseases
View Paper: https://www.semanticscholar.org/paper/81c53a84eb919e84c6c7421230a57aed12acb9c8
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In Infectious Diseases
Citations in the corpus
- COVID-19 and comorbidities: Deleterious impact on infected patients (2020, background): “This preactivation of S protein allows the viral entry into the cell and escapes from the human immune system [10].”
- Mechanisms of SARS-CoV-2 Transmission and Pathogenesis (2020, positive): “The presence of a unique furin cleavage site at the S1/S2 junction of SARS-CoV-2 Spike is also suspected to enhance human transmission events, although this remains to be further investigated [17,18].”