In the summer of 2020, half a year into the coronavirus pandemic, researchers traveled into the forests of northern Laos to catch bats that could accommodate close cousins to the pathogen.
At night, they used the fog net and canvas traps to catch the animals as they emerged from nearby caves, collected samples of saliva, urine and feces and then released them back into the dark.
Fecal samples were found to contain coronavirus, which the researchers examined in high-security biosafety laboratories, known as BSL-3, using specialized protective equipment and air filters.
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Three of the Laos coronaviruses were unusual: they carried a molecular hook on their surface that was very similar to the hook on the virus that causes Covid-19, called SARS-CoV-2. Like SARS-CoV-2, their hook allowed them to lock onto human cells.
“It’s even better than early strains of SARS-CoV-2,” said Marc Eloit, a virologist at the Pasteur Institute in Paris, who led the study, referring to how well the hook on Laos coronavirus binds to human cells. The study was posted online last month and has not yet been published in a scientific journal.
Virus experts buzz with the discovery. Some suspect that these SARS-CoV-2-like viruses can already infect humans from time to time and cause only mild and limited outbreaks. But under the right circumstances, the pathogens could give rise to a Covid-19-like pandemic, they say.
The results also have significant implications for the charged debate over Covid’s origins, 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 flood from an animal. But the new findings suggest otherwise.
“It really puts a notion that this virus should have been compounded or somehow manipulated in a laboratory, to be so good at infecting humans,” said Michael Worobey, a virologist from the University of Arizona who did not was involved in the work.
These bat viruses, along with more than a dozen others discovered in recent months in Laos, Cambodia, China and Thailand, may also help researchers better predict future pandemics. The virus’ family trees provide tips on where potentially dangerous strains lurk and what animals researchers should look at to find them.
Last week, the US government announced a $ 125 million project to identify thousands of wild viruses in Asia, Latin America and Africa to determine their risk of flooding. Dr. Eloit predicted that there were many more relatives of SARS-CoV-2 left to find.
“I’m a fly fisherman,” he said. “When I can not catch a trout, it does not mean there are no trout in the river.”
When SARS-CoV-2 first emerged, the closest known relative was a bat coronavirus, which Chinese researchers found in 2016 in a mine in southern China’s Yunnan province. RaTG13, as it is known, shares 96 percent of its genome with SARS-CoV-2. Based on the mutations from each virus, researchers have estimated that RaTG13 and SARS-CoV-2 share a common ancestor that infected bats about 40 years ago.
Both viruses infect cells by means of a molecular hook, called the “receptor binding domain”, to lock onto their surface. The RaTG13 hook, which is adapted for attachment to bat cells, can only weakly adhere to human cells. The hook of SARS-CoV-2, on the other hand, can strain cells in the human airway, the first step toward a potentially fatal case of Covid-19.
To find other close relatives of SARS-CoV-2, wildlife virus experts checked their freezers full of old samples from around the world. They identified several similar coronaviruses from southern China, Cambodia and Thailand. Most came from bats, while a few came from barking mammals known as pangolins. No one was a close relative other than RaTG13.
Dr. Eloit and his colleagues went out instead to find new coronaviruses.
They traveled to northern Laos, about 150 miles from the mine, where Chinese researchers had found RaTG13. Over six months, they caught 645 bats belonging to 45 different species. The bats had two dozen kinds of coronavirus, three of which were strikingly 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 viruses from Laos, as many as 16 were identical – the closest match to date.
Dr. Eloit speculated that one or more of the coronaviruses may be capable of infecting humans and causing mild illness. In a separate study, he and colleagues took blood samples from people in Laos who collect bat guano for a living. Although the Laotians showed no evidence of being infected with SARS-CoV-2, they carried immune markers, called antibodies, that appeared to be caused by a similar virus.
Linfa Wang, a molecular virologist at Duke-NUS Medical School in Singapore who was not involved in the study, agreed that such an infection was possible as the newly discovered viruses can adhere closely to a protein on human cells called ACE2.
“If the receptor binding domain is ready to use ACE2, these guys are dangerous,” said Dr. Wang.
Paradoxically, some other genes in the three Laotian viruses are more distantly related to SARS-CoV-2 than other bat viruses. The reason for this genetic patchwork is the complex development of coronavirus.
If a bat infected with a coronavirus catches another, the two different viruses can end up in a single cell at once. As the cell begins to replicate each of these viruses, their genes mix together and produce new virus hybrids.
In the Laotian coronaviruses, this remix has given them a receptor binding domain very similar to SARS-CoV-2. The original genetic exchange took place about a decade ago, according to a preliminary analysis by Spyros Lytras, a graduate student at the University of Glasgow in Scotland.
Sir. Lytras and his colleagues are now comparing SARS-CoV-2 not only with the new viruses from Laos, but with other close relatives found in recent months. They find even more signs of remixing. This process – known as recombination – can reshape viruses from year to year.
“It’s becoming more and more clear how important recombination is,” Lytras said.
He and his colleagues are now drawing the cluttered evolutionary trees of SARS-CoV-2-like viruses based on these new insights. Finding more viruses can help clear up the picture. But researchers disagree on where to look for them.
Dr. Eloit believes the best bid is a zone in Southeast Asia that includes the site where his colleagues found their coronavirus, as well as the nearby mine in Yunnan, where RaTG13 was found.
“I think the main landscape is similar to northern Vietnam, northern Laos and southern China,” said Dr. Eloit.
The US government’s new virus-hunting project, called DEEP VZN, may show one or more SARS-CoV-2-like viruses in that region. A spokesman for USAID, the agency that funded the effort, named Vietnam one of the countries where researchers will search, saying new coronaviruses are one of their top priorities.
Other researchers believe it is worth looking for relatives of SARS-CoV-2 further afield. Dr. Worobey of the University of Arizona said some coronavirus bats with SARS-CoV-2-like segments have been found in eastern China and Thailand.
“The recombination clearly shows that these viruses are part of a single gene pool over hundreds and hundreds of miles, if not thousands of miles,” said Dr. Worobey.
Colin Carlson, a biologist at Georgetown University, suggests that a virus capable of producing a Covid-like outbreak might be lurking even further afield. Bats as far east as Indonesia and as far west as India, he noted, share many biological traits with the animals known to carry SARS-CoV-2-like viruses.
“This is not just a problem in Southeast Asia,” said Dr. Carlson. “These viruses are different and they are more cosmopolitan than we thought.”
Interest in the origins of the pandemic has drawn new attention to the precautionary measures taken by researchers when studying potentially dangerous viruses. To win DEEP VZN grants, researchers must present a biosafety and biosafety plan, according to a spokesman for USAID, including staff training, guidelines for protective equipment to be worn in the field, and safety measures for laboratory work.
If researchers find more close cousins to SARS-CoV-2, it does not necessarily mean that they pose a deadly threat. They may not spread in humans or cause, as some researchers speculate, only small outbreaks. Only seven coronaviruses are known to have broken the species barrier to become well-established human pathogens.
“There are probably a large number of other coronaviruses that end up going nowhere,” said Jessica Metcalf, an evolutionary ecologist at Princeton University.
Still, recombination may make a virus that goes nowhere 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 been monitoring for decades that we think of as just something our pets can get can jump – we should have seen it coming, right?” Dr. Carlson said.