̽��ֱ�� of Cambridge - Stephen Graham

Study identifies genetic changes likely to have enabled SARS-CoV-2 to jump from bats to humans

jg533 — Fri, 08 Jan 2021 14:56:53 +0000

̽��ֱ��genetic adaptions 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 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 which potentially pose a pandemic threat.

“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,” said Dr Stephen Graham in the ̽��ֱ�� of Cambridge’s Department of Pathology, who was involved in the study.

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

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

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

̽��ֱ��results, published in the journal 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.

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. ̽��ֱ��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 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.

“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 Graham.

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.

This 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.

Reference
Conceicao, C et al: ‘ ̽��ֱ��SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins’. PLOS Biology, Dec 2020. DOI:10.1371/journal.pbio.3001016

Adapted from a press release by the Pirbright Institute

A new study, involving the ̽��ֱ�� of Cambridge and led by the Pirbright Institute, has identified key genetic changes in SARS-CoV-2 - the virus that causes COVID-19 - that may be responsible for the jump from bats to humans, and established which animals have cellular receptors that allow the virus to enter their cells most effectively.

It is 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

Stephen Graham

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Horseshoe bats

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Subterfuge, double agents and viruses

cjb250 — Fri, 20 Feb 2015 15:26:02 +0000

This is a tale of subterfuge and double agents, of armed struggle against an invading force and of defensive weapons being turned against their makers. But these events are happening much closer to home than you could ever imagine—these are battles fought every day within our very own bodies.
̽��ֱ��protagonists in this struggle are viruses, which seek to exploit the resource-rich environment of our cells, and every single cell in our body, whose very survival depends on their ability to repel these viral invaders.

Viruses are masters of subterfuge, blagging their way into cells and once inside hijacking the cell’s resources in a relentless quest to generate more copies of themselves. Cells possess innate defences against viral colonisation: they can raise the alarm, warning nearby cells when they have succumbed to infection, and can sacrifice themselves, depriving the virus of a host. But recent work from the Department of Pathology in Cambridge has revealed that poxviruses have acquired genes that once formed part of the host cell’s immune defences and have turned them to serve the virus’s own ends, acting as double-agents to deceive our immune system.

When it comes to the subtle art of immune evasion poxviruses are undoubtedly masters. ̽��ֱ��most notorious poxvirus is variola virus, which caused smallpox until its successful eradication in 1979 following a heroic immunisation campaign by the World Health Organisation. ̽��ֱ��DNA genomes of poxviruses contain roughly 200 genes. While this is many more than Ebola virus, which gets by with just seven genes in total, it is dwarfed by the 20,000 or so genes that make up you and me.

̽��ֱ��poxvirus genome encodes all the components necessary for poxviruses to invade cells, make abundant copies of themselves, and ensure these copies escape the infected cells so they can go off and colonise further cells. However, half of these 200 genes exist for the sole purpose of thwarting the body’s attempts to prevent infection or to limit the damage caused once infection is established.

Perhaps the most dramatic response of our cells to viral infection is to self-destruct, depriving the virus of a host and thus stopping the infection from spreading. This selfless act is called “apoptosis”. ̽��ֱ��triggering of apoptosis is regulated in our bodies by a finely tuned system of pro-death and pro-survival molecules. Unsurprisingly, viruses want to defuse the cell’s apoptosis bomb and make sure host cells survive long enough for the virus to replicate. When my colleagues determined the three-dimensional structure of the poxvirus protein called N1 they saw that it looked almost identical to the cellular pro-survival molecules that regulate apoptosis. Our studies showed that N1 is indeed a viral ‘apoptosis bomb disposal expert’ – it functions as a pro-survival gene, ensuring that cells refrain from self-destruction even when they know that they are infected.

But inhibiting apoptosis is not the only means by which poxviruses deter the host’s attempts to limit viral infection. When cells realise they have become infected by a virus they produce messenger molecules to warn nearby cells of the imminent danger. They do this by turning on transcription factors—regulators of gene activity. One transcription factor, NF-κB, is the Big Red Button of cellular signalling: when this is switched on the full armada of the body’s immune defences is recruited to the site of infection. It is roughly equivalent to the cell calling in air support.

Recently we solved the three-dimensional structure of a poxvirus protein called A49 that jams the NF-κB signal. Amazingly, we found that A49 also looks very similar to the cellular pro-survival molecules that regulate apoptosis, despite having a completely different function in cells. Furthermore, we also found that the protein we’d previously studied, N1, is able to jam the NF-κB signal in addition to its ability to block apoptosis.

Our findings with N1, A49 and other poxvirus proteins led us to wonder: is the similarity of these proteins to cellular pro-survival molecules more than just a coincidence? We know that the structures of proteins are conserved when those proteins descend from a common ancestor gene; it’s like the facial similarities you’d expect if looking through a family photo album.

To test whether the poxvirus proteins share a common ancestor, we systematically compared them with all the cellular pro-survival molecules that regulate apoptosis. We found that all poxvirus proteins do indeed lie on a single branch of this evolutionary tree, distinct from the branches containing host-cell proteins. This suggests that an ancestral poxvirus first acquired from its host a gene that had pro-survival activity against apoptosis, and that over the course of the evolutionary struggle between poxviruses and their unwelcoming hosts the virus has duplicated this gene and adapted it to have additional, useful functions.

Our work emphasises how evolutionary pressure can very finely tune a virus to the immune system of their host. Poxviruses have evolved multiple, specialised genes to block the various mechanisms used by our cells to respond to infection or warn nearby cells of the danger. But with such specialisation comes restrictions: unlike efficient viruses like Rabies, which infect a whole slew of warm-blooded mammals, the host range of the smallpox virus was limited to humans (the fact that allowed for its successful eradication).

Just as a master strategist will learn from his enemy, so medical researchers may learn from the evolved specialisation of pathogens like poxviruses. By investigating the manner in which poxviruses evade the host immune system, learned by trial and error over the course of thousands of years in their struggle against our bodies’ immune defences, we will gain unexpected insights into how our immune systems work, which may lead to the development of new drugs. What is more, we might also find viral genes that could be used to rein in hyperactive immune systems that cause autoimmune diseases like arthritis. Viruses are not the only ones who can turn genes into double-agents.

Dr Stephen Graham is a Sir Henry Dale Fellow, funded by the Wellcome Trust and the Royal Society, in the Department of Pathology at the ̽��ֱ�� of Cambridge.

Reference
Vaccinia Virus Protein A49 is an Unexpected Member of the B-cell Lymphoma (Bcl)-2 Protein Family

Every moment of every day, our immune systems are battling to keep us healthy against an onslaught from invading organisms. But some of these invaders have evolved to use our very defences against us, writes Dr Stephen Graham, a Sir Henry Dale Fellow.

Viruses are masters of subterfuge, blagging their way into cells and once inside hijacking the cell’s resources in a relentless quest to generate more copies of themselves

Stephen Graham

Wellcome Images

A human hand with smallpox pustules. Coloured etching by W.T. Strutt.

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