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Covid-19: Genetic changes that may have enabled SARS-CoV-2 to leap from bats to humans uncovered

A year on from the start of the Covid-19 outbreak, there remains uncertainty about how the SARS-CoV-2 virus came to infect humans.

It is believed to have originated in bats, and scientists do have the genetic sequence of a related bat coronavirus called RaTG13, which has 96 per cent similarity to the SARS-CoV-2 genome.

The SARS-CoV-2 virus that causes Covid-19 may have originated as a coronavirus in bats, then leapt to humans via an intermediate host
The SARS-CoV-2 virus that causes Covid-19 may have originated as a coronavirus in bats, then leapt to humans via an intermediate host

However, what is not known is the identity of any intermediate host that may have enabled it to jump from bats to humans, as no immediately related viruses have been found in animals.

Now a new study, involving the University of Cambridge and led by the Pirbright Institute, has identified key genetic changes in SARS-CoV-2 - centred around its spike protein - that could have enabled this jump.

And the study has also established which animals have cellular receptors that allow the virus to enter their cells most effectively.

Dr Stephen Graham in the University of Cambridge’s Department of Pathology, who was involved in the research, said: “This study used a non-infectious, safe platform to probe how spike protein changes affect virus entry into the cells of different wild, livestock and companion animals, something we will need to continue monitoring closely as additional SARS-CoV-2 variants arise in the coming months.”

In the 2002-3 SARS epidemic, scientists were able to identify closely related isolates of that coronavirus in both horseshoe bats, in which it originated, and civets, which are understood to have acted as intermediate hosts via a wild animal market.

Writing in PLOS Pathogens journal in November 2017, scientists at the Wuhan Institute of Virology in China warned: “The risk of spillover into people and emergence of a disease similar to SARS is possible...”

So it proved. The genetic adaptations identified by the new study were similar to those made by SARS-CoV, which caused SARS - a disease that claimed 800 lives.

It suggests a common mechanism may enable this family of viruses to mutate in order to jump from animals to humans.

This knowledge could be key to future research identifying viruses circulating in animals that could adapt to infect humans - known as zoonoses - and which could pose a pandemic threat.

The study compared the spike proteins of both SARS-CoV 2 virus and the RaTG13 virus that infects bats.

Spike proteins in SARS-CoV-2 and other coronaviruses are used to gain entry to cells by binding to surface receptors - such as a key one known as ACE2.

An illustration of the SARS-CoV-2 virus. Picture: Alissa Eckert, MS; Dan Higgins, MAMS; CDC
An illustration of the SARS-CoV-2 virus. Picture: Alissa Eckert, MS; Dan Higgins, MAMS; CDC

The relationship between the protein and receptor is akin to a lock and key. The spike protein must be the right shape to fit the cell’s receptors.

Each animal has receptors of a slightly different shape, meaning the spike protein binds to some better than others.

Using editing techniques not involving the live virus, the scientists swapped regions between the two and examined how well the resulting spike proteins could bind to human ACE2 receptors.

They found SARS-CoV-2 spikes containing RaTG13 regions were unable to bind to human ACE2 receptors effectively.

The RaTG13 spikes containing SARS-CoV-2 regions, however, could bind more efficiently to human receptors, although not to the same level as the unedited SARS-CoV-2 spike protein that is causing the pandemic.

The results, published in the journal PLOS Biology, suggest similar changes in the SARS-CoV-2 spike protein occurred historically. This may have played an important role in allowing the virus to jump the species barrier.

They also explored whether the SARS-CoV-2 spike protein could bind to ACE2 receptors in 22 animal species to assess their potential susceptibility to infection.

Bat and bird receptors had the weakest interactions with SARS-CoV-2.

The finding in bats further suggests SARS-CoV-2 adapted its spike protein when it jumped from bats into people, potentially via an intermediate host.

The animals receptors that interacted most strongly with the SARS-CoV-2 spike protein were those from dogs, cats and cattle. This efficient entry into cells could mean these animals could be more easily infected with the virus, although the researchers stress that receptor binding is only the first step in viral transmission between animal species.

Susceptibility to infection and ability to infect others is also infected by other factors, including whether SARS-CoV-2 can replicate once inside cells and the animal’s ability to fight off the virus.

“As we saw with the outbreaks in Danish mink farms last year, it’s essential to understand which animals can be infected by SARS-CoV-2 and how mutations in the viral spike protein change its ability to infect different species,” said Dr Graham.

The researchers say further studies are needed to understand whether livestock and pets could be receptive to Covid-19 infection from humans and act as reservoirs for the disease.

Dr Dalan Bailey, head of the viral glycoproteins group at Pirbright, said: “Uncovering the common traits that allow viruses to jump between animals and humans helps us to identify potential reservoirs of disease and forewarn us of future threats.”

The research was funded by the Medical Research Council, the Biotechnology and Biological Sciences Research Council and Innovate UK - all part of UK Research and Innovation - the Royal Society and Wellcome.

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