What Allows Bat Coronavirus RaTG13 To Use Human ACE2 Receptor? (Biology)

Since its first occurence in Wuhan, SARS-CoV-2 has infected more than 170 million people by June 2021, with more than 3.55 million confirmed deaths attributed to COVID-19, making it one of the deadliest pandemics in history.

In 2013, bat virus RaTG13 sampled from a Rhinolophus affinis horseshoe bat in Yunnan has been identified as the closest relative of SARS-CoV-2 showing approximately 96% sequence identity throughout the genome. Thus, SARS-CoV-2 most likely originated from horseshoe bats, although it has been proposed that cross-species transmission to humans may have involved pangolins as secondary intermediate host.

But, though the RaTG13 spike (S) protein is highly similar to the SARS-CoV-2 S it does not interact efficiently with the human ACE2 receptor, suggesting that this bat virus would most likely not be able to directly infect humans. But, Fabian Zech and colleagues now showed that mutation of T403R strongly enhances the ability of the bat RaTG13 spike protein to utilize ACE2 for infection of human cells and intestinal organoids.

“Our results demonstrate that a single amino acid change of T403R allows RaTG13, the closest known bat relative of SARS-CoV-2, to utilize human ACE2 for viral entry.”

They also suggested that, the strong enhancing effect of the T403R, likely came from a positively charged amino acid at position 403 in the spike protein, which was most likely a prerequisite for efficient zoonotic transmission and pandemic spread of SARS-CoV-2.

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Fig 1: SARS-CoV-2 S and T403R RaTG13 S allow entry with human but not bat ACE2. (a) HEK293T cells expressing indicated ACE2 (Human ACE2 or Rhinolophus affinis ACE2) constructs or (b) , Tb 1 Lu, Tadarida brasiliensis derived lung epithelial and Ri 1 Lu huACE2 Rhinolophus affinis derived lung epithelial cells expressing human ACE2 were infected with VSVΔG-GFP pseudotyped with SARS-CoV-2, RaTG13 or indicated mutant S. Quantification by automatic counting of GFP positive cells. n=3 (biological replicates) ± SEM. P values are 457 indicated (student’s t test). © Zech et al.

Finally, they found that a positively charged residue at the corresponding position is present in the spike proteins of the great majority of RaTG13-related bat coronaviruses (as shown in Fig. 2) raising the possibility that many bat sarbecoviruses, including the 148 unknown precursor of SARS-CoV-2, are fitter for zoonotic transmission than RaTG13.

Fig 2: Conservation of the RGD motif in bat Coronavirus Spike proteins. (a) Sequence logo of the alignment of 137 different bat Coronavirus Spike RBD sequences. The 493 RGD motif is highlighted by a red box. (b) Primary sequence alignment of selected bat 494 coronaviruses, human coronaviruses and SARS-CoV-2 strains. The RGD motif is highlighted 495 in bold. © Zech et al.

Reference: Fabian Zech, Daniel Schniertshauer, Christoph Jung, Alexandra Herrmann, Qinya Xie, Rayhane Nchioua, Caterina Prelli Bozzo, Meta Volcic, Lennart Koepke, Jana Krueger, Sandra Heller, Alexander Kleger, Timo Jacob, Karl-Klaus Conzelmann, Armin Ensser, Konstantin Maria Johannes Sparrer, Frank Kirchhoff, “Spike mutation T403R allows bat coronavirus RaTG13 to use human ACE2”, bioRxiv 2021.05.31.446386; doi: https://doi.org/10.1101/2021.05.31.446386

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