Receptor utilization of angiotensin-converting enzyme 2 (ACE2) indicates a narrower host range of SARS-CoV-2 than that of SARS-CoV

Coronavirus (CoV) pandemics have become a huge threat to the public health worldwide in the recent decades. Typically, severe acute respiratory syndrome CoV (SARS-CoV) caused SARS pandemic in 2003 and SARS-CoV-2 caused the ongoing COVID-19 pandemic. Both viruses are most likely originated from bats. Thus, direct or indirect inter-species transmission from bats to humans is required for the viruses to cause pandemics. Receptor utilization is a key factor determining the host range of viruses which is critical to the inter-species transmission. Angiotensin-converting enzyme 2 (ACE2) is the receptor of both SARS-CoV and SARS-CoV-2, but only ACE2s of certain animals can be utilized by the viruses. Here, we employed pseudovirus cell-entry assay to evaluate the receptor-utilizing capability of ACE2s of 20 animals by the two viruses and found that SARS-CoV-2 utilized less ACE2s than SARS-CoV, indicating a narrower host range of SARS-CoV-2. Especially, SARS-CoV-2 tended not to use murine or non-mammal ACE2s. Meanwhile, pangolin-CoV, another SARS-related coronavirus highly homologous to SARS-CoV-2 in its genome, yet showed similar ACE2 utilization profile with SARS-CoV rather than SARS-CoV-2. Nevertheless, the actual susceptibility of these animals to the coronaviruses should be further verified by in vivo studies. To clarify the mechanism underlying the receptor utilization, we compared the amino acid sequences of the 20 ACE2s and found 5 amino acid residues potentially critical for ACE2 utilization, including the N-terminal 20th and 42nd amino acid residues that might determine the different receptor utilization of SARS-CoV, SARS-CoV-2 and pangolin-CoV. Our studies enhance the understanding of receptor utilization of pandemic coronaviruses, potentially contributing to the virus tracing, intermediate host screening and epidemic prevention for pathogenic coronaviruses.

Automated summary

This study found that SARS-CoV-2 utilizes less ACE2 receptors than SARS-CoV, showing a narrower host range and a tendency to not use murine or non-mammal ACE2 receptors. Additionally, pangolin-CoV is more similar in ACE2 utilization profile to SARS-CoV than to SARS-CoV-2. Further in vivo studies are needed to verify the actual susceptibility of these animals to coronaviruses. The comparison of amino acid sequences of ACE2 receptors revealed potentially critical residues determining the varying receptor utilization of SARS-CoV, SARS-CoV-2, and pangolin-CoV. This research enhances understanding of the receptor utilization of pandemic coronaviruses, aiding in virus tracing, intermediate host screening, and epidemic prevention for pathogenic coronaviruses.