Australian researchers studying SARS-CoV-2 have discovered that the virus is most ideally adapted to infect human cells — instead of bat or pangolin cells, prompting renewed questions about its origin.
The scientists, from Flinders University and La Trobe University, described how they used high-performance computer modelling of SARS-CoV-2’s structure at the beginning of the pandemic to predict its ability to infect humans and a range of 12 domestic and exotic animals.
They were hoping to identify an intermediate animal vector that may have played a role in transmitting a bat virus to humans, and to understand any risk posed by the susceptibilities of pets and livestock.
Using genomic data from 12 animal species, the researchers painstakingly built computer models of the key ACE2 protein receptors for each species. These models were then used to calculate how strongly the SARS-CoV-2 spike protein bound to each species’ ACE2 receptor.
Surprisingly, the results showed that SARS-CoV-2 bound to ACE2 on human cells more tightly than any of the tested animal species, including bats and pangolins. If one of the animal species tested was the origin, it would normally be expected to show the highest binding to the virus.
“Humans showed the strongest spike binding, consistent with the high susceptibility to the virus, but very surprising if an animal was the initial source of the infection in humans,” said Professor David Winkler at La Trobe University.
The findings, originally released on the ArXiv preprint server, have now been peer reviewed and published in Scientific Reports.
“The computer modelling found the virus’s ability to bind to the bat ACE2 protein was poor relative to its ability to bind human cells. This argues against the virus being transmitted directly from bats to humans. Hence, if the virus has a natural source, it could only have come to humans via an intermediary species which has yet to be found,” says Flinders affiliated Professor Nikolai Petrovsky.
The team’s computer modelling also showed fairly strong binding of SARS-CoV-2 to ACE2 from pangolins, which are occasionally used as food or in traditional medicines. Professor Winkler noted that pangolins displayed the highest spike binding energy of all the animals in the study – significantly higher than bats, monkeys and snakes.
“While it was incorrectly suggested early in the pandemic by some scientists that they had found SARS-CoV-2 in pangolins, this was due to a misunderstanding and this claim was rapidly retracted as the pangolin coronavirus they described had less than 90% genetic similarity to SARS-CoV-2 and hence could not be its ancestor,” Prof Petrovsky said.
Similarity in spike proteins
As shown in this and other studies, the specific part of the pangolin coronavirus spike protein that binds to ACE2 was almost identical to its SARS-CoV-2 counterpart.
“This sharing of the almost identical spike protein almost certainly explains why SARS-CoV-2 binds so well to pangolin ACE2. Pangolin and SARS-CoV-2 spike proteins may have evolved similarities through a process of convergent evolution, genetic recombination between viruses, or through genetic engineering, with no current way to distinguish between these possibilities,” Prof Petrovsky said.
“Overall, putting aside the intriguing pangolin ACE2 results, our study showed that the COVID-19 virus was very well adapted to infect humans.”
“We also deduced that some domesticated animals like cats, dogs and cows are likely to be susceptible to SARS-CoV-2 infection too,” Prof Winkler added.
The question of how the virus came to infect humans currently has two main explanations. The virus may have jumped to humans from bats through an intermediary animal which remains to be identified. The other explanation making headlines in the media is an accidental release from a virology lab, where it perhaps was created in ‘gain of function‘ tests, which are carried out around the world to better understand pathogens. A number of organisations and governments, including the World Health Organization and the United States have urged further investigation to find out which of these is correct — though a definitive answer may take years.
How and where the SARS-CoV-2 virus adapted to become such an effective human pathogen remains a mystery, the researchers concluded, adding that finding the origins of the disease will help efforts to protect humanity against future coronavirus pandemics.
Source: EurekAlert!
Journal information: Sakshi Piplani et al, In silico comparison of SARS-CoV-2 spike protein-ACE2 binding affinities across species and implications for virus origin, Scientific Reports (2021). DOI: 10.1038/s41598-021-92388-5
