Abstract
The bat sarbecovirus RaTG13 is a close relative of SARS-CoV-2, the cause of the COVID-19 pandemic. However, this bat virus was most likely unable to directly infect humans since its Spike (S) protein does not interact efficiently with the human ACE2 receptor. Here, we show that a single T403R mutation increases binding of RaTG13 S to human ACE2 and allows VSV pseudoparticle infection of human lung cells and intestinal organoids. Conversely, mutation of R403T in the SARS-CoV-2 S reduces pseudoparticle infection and viral replication. The T403R RaTG13 S is neutralized by sera from individuals vaccinated against COVID-19 indicating that vaccination might protect against future zoonoses. Our data suggest that a positively charged amino acid at position 403 in the S protein is critical for efficient utilization of human ACE2 by S proteins of bat coronaviruses. This finding could help to better predict the zoonotic potential of animal coronaviruses.
Highlights
The bat sarbecovirus RaTG13 is a close relative of SARS-CoV-2, the cause of the COVID-19 pandemic
We found that R403 is highly conserved in SARS-CoV-2 S proteins: only 294 of ~3.4 million S sequences recorded on GSAID contain a conservative change of R403K and just 132 another amino acids: M (78), H (16), G (10), S (10), T (6), I (9), L (2), N (2), P (1) or W (1)
Our results demonstrate that a single amino acid change of T403R allows the S protein of RaTG13, one of the closest known bat relatives of SARS-CoV-2, to utilize human angiotensin-converting enzyme 2 (ACE2) for viral entry
Summary
The bat sarbecovirus RaTG13 is a close relative of SARS-CoV-2, the cause of the COVID-19 pandemic. This bat virus was most likely unable to directly infect humans since its Spike (S) protein does not interact efficiently with the human ACE2 receptor. Our data suggest that a positively charged amino acid at position 403 in the S protein is critical for efficient utilization of human ACE2 by S proteins of bat coronaviruses. The RaTG13 S protein is highly similar to the SARS-CoV-2 S it does not interact efficiently with the human ACE2 receptor[11], suggesting that this bat virus would most likely not be able to infect humans directly. We show, which specific features allow the S proteins of bat CoVs to use human ACE2 for efficient entry and to successfully cross the species barrier to humans
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