Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is thought to have originated in bats, but how it jumped hosts to infect humans is unclear, as is the potential for the virus to infect other animal species. Researchers from The Pirbright Institute have identified key differences in SARS-CoV-2 that may be responsible for the jump from bats to humans, as well as establishing which animals have cellular receptors that allow the virus to enter most effectively.
Identifying the source of the COVID-19 outbreak has been challenging because no immediately related coronaviruses have been found in animals. The closest known relative is a bat coronavirus, RaTG13, which shares 96 percent similarity to the SARS-CoV-2 genome. The team, led by Dr Dalan Bailey, compared the genomes of both viruses and identified several important regions that differed between their spike proteins, which the virus uses to bind to the ACE2 surface receptors of cells to gain entry.
To examine whether these differences were involved in the adaptation of SARS-CoV-2 to humans, scientists swapped these regions and examined how well the resulting spike proteins bound to human ACE2 receptors using a method that does not involve live virus.
The results, published in PLOS Biology, showed SARS-CoV-2 spikes containing RaTG13 regions were unable to bind to human ACE2 receptors effectively while the RaTG13 spikes containing SARS-CoV-2 regions could bind more efficiently to human receptors, although not to the same level as the unedited SARS-CoV-2 spike protein. This potentially indicates that similar changes in the SARS-CoV-2 spike protein occurred historically, which may have played a key role in allowing the virus to jump the species barrier.
The team noted that these genetic adaptions were similar to those made by severe acute respiratory syndrome coronavirus (SARS-CoV) when it adapted from bats to infect humans. This suggests that there may be a common mechanism by which this family of viruses mutates in order to jump 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 potentially pose a pandemic threat.
Researchers also investigated whether the SARS-CoV-2 spike protein could bind to the ACE2 receptors from 22 different animals to ascertain which of these, if any, may be susceptible to infection. They demonstrated that bat and bird receptors made the weakest interactions with SARS-CoV-2. The lack of binding to bat receptors adds weight to the evidence that SARS-CoV-2 likely adapted its spike protein when it jumped from bats into people, possibly via another animal (known as an intermediate host).
Dog, cat, and cattle ACE2 receptors were identified as the strongest interactors with the SARS-CoV-2 spike protein. Efficient entry into cells could mean that infection may be more easily established in these animals, although receptor binding is only the first step in viral transmission between different animal species.
An animal’s susceptibility to infection and its subsequent ability to infect others is reliant on a range of factors including whether SARS-CoV-2 is able to replicate once inside cells and the animal’s ability to fight off the virus. Further studies are needed to understand whether livestock and companion animals could be receptive to COVID-19 infection from humans and act as reservoirs for this disease.
Dr Dalan Bailey, head of the Viral Glycoproteins Group at Pirbright, said: “Using molecular techniques to study coronavirus spike proteins in isolation, without ever needing to work with the SARS-CoV-2 virus, has enabled us to take an in depth look at how genetic differences in coronavirus spike proteins and animal ACE2 receptors influence which animals the virus may be able to infect. 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.”
Notes to editors
The paper titled The SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins can be found on the PLOS Biology website: https://doi.org/10.1371/journal.pbio.3001016
This research was funded by the Medical Research Council (MRC) the Biotechnology and Biological Sciences Research Council (BBSRC) and Innovate UK, all part of UK Research and Innovation (UKRI), the Royal Society and Wellcome Trust.
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About The Pirbright Institute
The Pirbright Institute is a world leading centre of excellence in research and surveillance of virus diseases of farm animals and viruses that spread from animals to humans. Based in the UK and receiving strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) part of UK Research and Innovation (UKRI), the Institute works to enhance capability to contain, control and eliminate these economically and medically important diseases through highly innovative fundamental and applied bioscience.
The Institute is an independent company, limited by guarantee and a registered charity, governed by a Board of non-executive Trustee Directors.
With an annual income of £35 million from grants and commercial activity, and a total of £25.2 million strategic investment from BBSRC UKRI during 2019-2020, the Institute contributes to global food security and health, improving quality of life for animals and people.
For more information about The Pirbright Institute see: www.pirbright.ac.uk
About BBSRC UKRI
The Biotechnology and Biological Sciences Research Council (BBSRC) is part of UK Research and Innovation (UKRI), a non-departmental public body funded by a grant-in-aid from the UK government.
BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.
Funded by government, BBSRC invested £451 million in world-class bioscience in 2019-20.
We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.
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