Study identifies genetic changes that probably allowed SARS-CoV-2 to pass from bats to humans

A new study, involving the University of Cambridge and led by the Pirbright Institute, identified important genetic changes in SARS-CoV-2 – the virus that causes COVID-19 – that may be responsible for the leap from bats to humans, and established which animals have cell receptors that allow the virus to enter their cells more effectively.

The genetic adaptations identified were similar to those made by SARS-CoV – which caused the 2002-2003 SARS epidemic – when it adapted from bats to infect humans. This suggests that there may be a common mechanism by which this family of viruses is mutated to pass from animals to humans. This understanding can be used in future research to identify viruses circulating in animals that could adapt to infect humans (known as zoonoses) and that potentially pose a pandemic threat.

“This study used a safe, non-infectious platform to investigate how changes in the peak protein affect the entry of the virus into the cells of different wild animals, livestock and companions, something we will need to continue to monitor closely as additional SARS variants emerge. -CoV-2 in the coming months, “said Dr. Stephen Graham, from the Department of Pathology at the University of Cambridge, who was involved in the study.

In the SARS epidemic of 2002-2003, scientists were able to identify closely related isolates in bats and civets – in which the virus is believed to have adapted to infect humans. However, in the current outbreak of COVID-19, scientists still do not know the identity of the intermediate host or have similar samples to analyze. But they have the sequence of a related bat coronavirus, called RaTG13, which shares 96% similarity to the SARS-CoV-2 genome. The new study compared the peak proteins of both viruses and identified several important differences.

SARS-CoV-2 and other coronaviruses use their peak proteins to gain entry into cells by binding to their surface receptors, for example, ACE2. Like a lock and key, the peak protein must be shaped to fit the cell’s receptors, but each animal’s receptors have a slightly different shape, which means that the peak protein binds to some better than than others.

To examine whether these differences between SARS-CoV-2 and RaTG13 were involved in adapting SARS-CoV-2 to humans, scientists switched these regions and examined how well these resulting peak proteins bound to human ACE2 receptors – using a method that does not involve the use of live viruses.

The results, published in the journal PLOS Biology, showed that the SARS-CoV-2 peaks containing RaTG13 regions were unable to bind to human ACE2 receptors effectively, while RaTG13 peaks containing SARS-CoV-2 regions could bind more efficiently to human receptors – although not at the same level as the unedited SARS -CoV-2 spike protein. This potentially indicates that similar changes in the SARS-CoV-2 spike protein have occurred historically, which may have played a key role in allowing the virus to bypass the species barrier.

The researchers also investigated whether the SARS-CoV-2 spike protein could bind to the ACE2 receptors of 22 different animals to determine which one, if any, may be susceptible to infection. They demonstrated that bat and bird receptors had the weakest interactions with SARS-CoV-2. The lack of binding to bat receptors adds weight to the evidence that SARS-CoV-2 probably adapted its peak protein when it leapt from bats to people, possibly through an intermediate host.

ACE2 receptors in dogs, cats and cattle have been identified as the strongest interacting with the SARS-CoV-2 spike protein. Efficient entry into cells may mean that infection can be more easily established in these animals, although binding to the receptor is only the first step in viral transmission between different animal species.

“As we saw with outbreaks in Danish mink farms last year, it is essential to understand which animals can become infected with SARS-CoV-2 and how mutations in the viral peak protein change their ability to infect different species,” said Graham.

An animal’s susceptibility to infection and its subsequent ability to infect others depends on a number of factors – including whether SARS-CoV-2 is able to replicate once inside cells and the animal’s ability to fight the virus . Further studies are needed to understand whether cattle and companion animals can be receptive to COVID-19 infection in humans and act as reservoirs for this disease.