ABSTRACT
The SARS-CoV-2 spike (S) protein, the viral mediator for binding and entry into the host cell, has sparked great interest as a target for vaccine development and treatments with neutralizing antibodies. Initial data suggest that the virus has low mutation rates, but its large genome could facilitate recombination, insertions, and deletions, as has been described in other coronaviruses. Here, we deep-sequenced the complete SARS-CoV-2 S gene from 18 patients (10 with mild and 8 with severe COVID-19), and found that the virus accumulates deletions upstream and very close to the S1/S2 cleavage site, generating a frameshift with appearance of a stop codon. These deletions were found in a small percentage of the viral quasispecies (2.2%) in samples from all the mild and only half the severe COVID-19 patients. Our results suggest that the virus may generate free S1 protein released to the circulation. We propose that natural selection has favored a “Don’t burn down the house” strategy, in which free S1 protein may compete with viral particles for the ACE2 receptor, thus reducing the severity of the infection and tissue damage without losing transmission capability.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Discussion section we have added: In a recent study (27), Lau et al reported the results of plaque purification of Vero-E6 cultured SARS-CoV-2 genomes obtained from nasopharyngeal aspirate of a COVID-19 patient. The authors found deletions of 10 to 15 nucleotides at the S1/S2 junction. In a further experiment, infection of hamsters with virus containing these variants led to attenuated viral disease. These findings strongly support our hypothesis that deletions close to the S1/S2 cleavage site may be a phenomenon favoured by natural selection to enhance spread of the SARS-CoV-2. The authors failed to detect these deletions in this and other clinical specimens, but this may be attributable to the relatively low sequencing throughput of the Sanger technique used. In the cell culture experiments, the lack of genomes with deletions that generate a premature stop codon in the S gene can be easily explained, as the truncated S gene would produce non-infectious particles.
