In the summer of 2020, six months after the start of the coronavirus pandemic, scientists traveled to the forests of northern Laos to catch bats that could harbor close cousins of the pathogen.
In the dead of night, they used mist nets and canvas traps to catch the animals as they exited nearby caves, collected saliva, urine and excrement samples, and then released them into darkness.
The fecal samples were found to contain coronaviruses, which scientists studied in high-security biosafety labs known as BSL-3 using specialized protective equipment and air filters.
Three of Laos’ coronaviruses were unusual: they carried a molecular hook on their surface very similar to the hook of the virus that causes COVID-19, called SARS-CoV-2. Like SARS-CoV-2, their hook allowed them to cling to human cells.
“It’s even better than the early strains of SARS-CoV-2,” said Marc Eloit, a virus expert at the Institut Pasteur in Paris who led the study, referring to how the fish hook Laos coronavirus binds to human cells. The study went online last month and has yet to be published in a scientific journal.
Virus experts are buzzing about the discovery. Some suspect that these SARS-CoV-2-like viruses can already infect people from time to time, causing only mild and limited outbreaks. But under the right circumstances, the pathogens could give rise to a COVID-19-like pandemic, they say.
The findings also have important implications for the busy debate over the origins of COVID, experts say. Some people have speculated that the impressive ability of SARS-CoV-2 to infect human cells could not have evolved through a natural overflow from an animal. But the new findings seem to suggest otherwise.
“It really puts to bed any idea that this virus had to be concocted or somehow manipulated in a lab to be so good at infecting humans,” said Michael Worobey, a virus expert from the ‘University of Arizona who was not involved in the work.
These bat viruses, along with more than a dozen others discovered in recent months in Laos, Cambodia, China and Thailand, could also help researchers better anticipate future pandemics. Virus family trees offer clues as to where potentially dangerous strains are hiding and which animals scientists should examine for them.
Last week, the U.S. government announced a $ 125 million project to identify thousands of wild viruses in Asia, Latin America and Africa to determine their risk of spread. Eloit predicted that there were many more SARS-CoV-2 relatives to be found.
“I’m a fly fisherman,” he says. “When I am unable to catch a trout, it does not mean that there are no trout in the river.”
When SARS-CoV-2 first appeared, its known closest relative was a bat coronavirus that Chinese researchers discovered in 2016 at a mine in southern China’s Yunnan province. RaTG13, as it is called, shares 96% of its genome with SARS-CoV-2. Based on the mutations carried by each virus, scientists estimated that RaTG13 and SARS-CoV-2 share a common ancestor that infected bats about 40 years ago.
Both viruses infect cells by using a molecular hook, called a “receptor binding domain,” to attach to their surface. The hook of RaTG13, adapted to attach to bat cells, can only weakly attach to human cells. The SARS-CoV-2 hook, on the other hand, can grab cells in the human airways, the first step towards a potentially fatal case of COVID-19.
To find other close relatives of SARS-CoV-2, wildlife virus experts checked their freezers filled with old samples from around the world. They identified several similar coronaviruses from southern China, Cambodia and Thailand. Most were from bats, while a few were from scaly mammals called pangolins. None was a closer relative than RaTG13.
Instead, Eloit and his colleagues set out to find new coronaviruses.
They traveled to northern Laos, about 150 miles from the mine where Chinese researchers found RaTG13. In six months, they captured 645 bats belonging to 45 different species. Bats harbored two dozen types of coronavirus, three of which were surprisingly similar to SARS-CoV-2 – especially in the receptor binding domain.
In RaTG13, 11 of the 17 key building blocks of the domain are identical to those of SARS-CoV-2. But in the three Laos viruses, as many as 16 were identical – the closest match to date.
Eloit hypothesized that one or more of the coronaviruses might be able to infect humans and cause mild illness. In a separate study, he and his colleagues took blood samples from people in Laos who collect bat guano for a living. Although the Laotians showed no signs of infection with SARS-CoV-2, they carried immune markers, called antibodies, which appeared to be caused by a similar virus.
Linfa Wang, a molecular virus expert at Duke-NUS Medical School in Singapore who was not involved in the study, agreed that such an infection was possible because newly discovered viruses can bind tightly to a protein. human cells called ACE2.
“If the receptor binding domain is ready to use ACE2, these types are dangerous,” Wang said.
Paradoxically, certain other genes of the three Laotian viruses are more distant from SARS-CoV-2 than other bat viruses. The cause of this genetic patchwork is the complex evolution of coronaviruses.
If a bat infected with a coronavirus catches a second one, the two different viruses can end up in one cell at a time. As this cell begins to replicate each of these viruses, their genes mix together, producing new virus hybrids.
In Laotian coronaviruses, this shuffling of genes gave them a receptor binding domain very similar to that of SARS-CoV-2. The original genetic exchange took place around a decade ago, according to a preliminary analysis by Spyros Lytras, a graduate student at the University of Glasgow in Scotland.
Lytras and his colleagues are now comparing SARS-CoV-2 not only to new viruses from Laos, but to other close relatives that have been found in recent months. They find even more evidence of genetic mixing. This process – known as recombination – can reshape viruses from year to year.
“It is becoming more and more evident how important recombination is,” Lytras said.
He and his colleagues are now drawing the disordered evolutionary trees of SARS-CoV-2-like viruses based on this new knowledge. Finding more viruses might help clarify the picture. But scientists are divided on where to look for them.
Eloit thinks the best bet is an area in Southeast Asia that includes the site where his colleagues found their coronaviruses, as well as the nearby Yunnan mine where RaTG13 was found.
“I think the main landscape is northern Vietnam, northern Laos, and southern China,” Eloit said.
The US government’s new virus hunt project, called DEEP VZN, could reveal one or more SARS-CoV-2-like viruses in this region. A spokesperson for USAID, the agency funding the effort, named Vietnam as one of the countries where researchers will conduct research and said the novel coronaviruses are one of their top priorities.
Other scientists believe it is worth looking for relatives of SARS-CoV-2 further. Worobey of the University of Arizona said some bat coronaviruses carrying SARS-CoV-2-like segments have been found in eastern China and Thailand.
“Obviously, recombination shows us that these viruses are part of a single gene pool for hundreds and hundreds of kilometers, even thousands of kilometers,” Worobey said.
Colin Carlson, a biologist at Georgetown University, suspects that a virus capable of producing a COVID-like epidemic could be lurking even further away. Bats as far east as Indonesia and as far west as India, he noted, share many biological characteristics with animals known to carry SARS-like viruses. CoV-2.
“It’s not just a Southeast Asian problem,” Carlson said. “These viruses are diverse and they are more cosmopolitan than we might think. “
Interest in the origins of the pandemic has drawn renewed attention to the safety measures researchers use when studying potentially dangerous viruses. To qualify for DEEP VZN grants, scientists will need to provide a biosecurity and biosecurity plan, according to a USAID spokesperson, including training for staff, guidelines on protective equipment to wear in the field, and safety measures for laboratory work.
If scientists find cousins closer to SARS-CoV-2, that doesn’t necessarily mean they pose a deadly threat. They might not spread to humans or, as some scientists speculate, only cause small outbreaks. Only seven coronaviruses are known to have crossed the species barrier to become well-established human pathogens.
“There’s probably a huge array of other coronaviruses that end up going nowhere,” said Jessica Metcalf, an evolutionary ecologist at Princeton University.
Yet recombination may be able to turn a virus that is going nowhere into a new threat. In May, researchers reported that two coronaviruses in dogs recombined in Indonesia. The result was a hybrid that infected eight children.
“When a coronavirus that we’ve watched for decades, which we think of as something our pets can catch, can take the leap, we should have seen it coming, right? Carlson said.
This article originally appeared in The New York Times.
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