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In the summer of 2020, six months into the coronavirus pandemic, scientists traveled to the forests of northern Laos to catch bats that may harbor close cousins of the pathogen.
In the dead of night, they used mist nets and canvas traps to catch animals emerging from nearby caves, collecting saliva, urine, and fecal samples, and then releasing them back into the dark.
The stool samples turned out to contain coronaviruses, which the scientists examined using special protective clothing and air filters in high-security biosafety laboratories known as BSL-3.
Three of the Laotian coronaviruses were unusual: They carried a molecular hook on their surface, very similar to the hook on the virus that causes Covid-19, called SARS-CoV-2. Like SARS-CoV-2, its hooks allowed it to attach to human cells.
“It’s even better than the early strains of SARS-CoV-2,” said Marc Eloit, a virologist at the Pasteur Institute in Paris, citing how well the hook on Laos coronaviruses attaches to human cells. Study sent It 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 may occasionally infect humans and cause only mild and limited outbreaks. But they say that under the right conditions, pathogens can lead to a Covid-19-like pandemic.
Experts say the findings also have important implications for the heated debate about the origins of Covid. some people have speculation He said SARS-CoV-2’s impressive ability to infect human cells could not have evolved through a natural spread from an animal. But new findings seem to suggest otherwise.
“This really refutes the idea that for the virus to be so good at infecting humans, it had to have been fabricated or somehow manipulated in a lab,” said Michael Worobey, a University of Arizona virologist who was not involved in the study.
These bat viruses, along with more than a dozen viruses discovered in Laos, Cambodia, China and Thailand in recent months, could help researchers better predict future outbreaks. Family trees of viruses provide clues as to where potentially dangerous strains are hiding and which animals scientists should look to to find them.
Last week, the US government announced $125 million. project detecting thousands of wild viruses in Asia, Latin America and Africa to identify their spread risks. Dr. Eloit surmised that there were many more SARS-CoV-2 relatives to be found.
“I’m a fly catcher,” he said. “If I can’t catch a trout, that doesn’t mean there aren’t any trout in the river.”
When SARS-CoV-2 first appeared, its closest known relative was a bat coronavirus that Chinese researchers found in 2016 at a mine in southern China’s Yunnan Province. As is known, RaTG13 shares 96 percent of its genome with SARS-CoV-2. Based on the mutations each virus carries, the scientists speculated that RaTG13 and SARS-CoV-2 share a common ancestor that infects bats. about 40 years ago.
Both viruses infect cells using a molecular hook called a “receptor binding site” to attach to their surface. The hook of RaTG13 adapted for attachment to bat cells is only weak hug to human cells. SARS-CoV-2’s hook, by contrast, can pinch cells in the human respiratory tract, the first step towards a potentially deadly case of Covid-19.
To find other close relatives of SARS-CoV-2, wildlife virus experts checked their freezers filled with ancient specimens from around the world. They detected several similar coronaviruses: Southern China, Cambodia, and Thailand. Most came from bats, and a few came from scaly mammals known as pangolins. None were more closely related than RaTG13.
Dr. Eloit and his colleagues started finding new coronaviruses instead.
They traveled to northern Laos, about 150 miles from the mine where Chinese researchers found RaTG13. They caught 645 bats belonging to 45 different species over six months. The bats harbored two dozen species of coronavirus, three of which were strikingly similar to SARS-CoV-2, particularly in the receptor-binding domain.
In RaTG13, 11 of the 17 fundamental 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 predicted that one or more coronaviruses could infect humans and cause mild illness. separate study, he and his colleagues took blood samples from people in Laos who collected bat dung for living. Although Laotians did not show signs of being infected with SARS-CoV-2, they carried immune markers called antibodies, which are understood to be caused by a similar virus.
Linfa Wang, a molecular virologist at the Duke-NUS School of Medicine in Singapore who was not involved in the study, agreed that such an infection is possible because the newly discovered viruses can bind tightly to a protein on human cells called ACE2.
Dr. “If the receptor binding site is ready to use ACE2, these guys are dangerous,” Wang said.
Paradoxically, several other genes in the three Laotian viruses are more distantly related to SARS-CoV-2 than to other bat viruses. The reason for this genetic patchwork is the complex evolution of coronaviruses.
If a bat infected with a coronavirus catches the latter, two different viruses can enter a single cell at the same time. As this cell begins to replicate each of these viruses, their genes are shuffled together and new virus hybrids are produced.
In Laotian coronaviruses, this gene shuffling gave them a receptor-binding site very similar to that of SARS-CoV-2. The original genetic swap took place nearly a decade ago, according to preliminary analysis by Spyros Lytras, a graduate student at the University of Glasgow in Scotland.
Mr. Lytras and colleagues are now comparing SARS-CoV-2 not only with new viruses from Laos, but also with other close relatives found in recent months. They find more evidence of gene shuffling. This process, known as recombination, may be reshaping viruses from year to year.
“It’s becoming increasingly clear how important recombination is,” said Mr Lytras.
He and his colleagues are now plotting complex evolutionary trees of SARS-CoV-2-like viruses based on these new insights. Finding more viruses might help clear up the picture. But scientists are divided on where to look for them.
Dr. Eloit believes the best bet is a Southeast Asian site that includes the site where his colleagues found their coronavirus and the nearby mine in Yunnan, where RaTG13 is located.
Dr. “I think the main landscape corresponds to northern Vietnam, northern Laos and southern China,” Eloit said.
The US government’s new virus-hunting project, DEEP VZN, may reveal one or more SARS-CoV-2-like viruses in that area. A spokesperson for USAID, the agency that funded the study, named Vietnam as one of the countries the researchers will investigate and said novel coronaviruses are one of its top priorities.
Other scientists think it’s worth looking for more distant relatives of SARS-CoV-2. University of Arizona’s Dr. Worobey said that some bat coronaviruses carrying segments similar to SARS-CoV-2 have been found in eastern China and Thailand.
Dr. “Clearly recombination shows us that these viruses are part of a single gene pool, across hundreds if not thousands of miles,” Worobey said.
Colin Carlson, a biologist at Georgetown University, suspects that a virus that could produce a Covid-like epidemic lurks even further away. He noted that as far east as Indonesia and as far west as India, bats share many biological characteristics with animals known to carry SARS-CoV-2-like viruses.
Dr. “This isn’t just a Southeast Asian issue,” Carlson said. “These viruses are diverse and more cosmopolitan than we thought.”
Interest in the origins of the pandemic has brought renewed attention to the safety precautions researchers use when studying potentially dangerous viruses. To win DEEP VZN grants, scientists will need to provide a biosecurity and biosecurity plan, according to a USAID spokesperson.
If scientists find closer cousins of SARS-CoV-2, that doesn’t necessarily mean they pose a deadly threat. They may fail to spread in humans or cause only minor epidemics, according to some scientists’ estimates. Only seven coronaviruses are known to have crossed the species barrier to become well-known human pathogens.
“There are probably lots of other coronaviruses that are not going anywhere,” said Jessica Metcalf, an evolutionary ecologist at Princeton University.
Yet recombination can turn a virus that went nowhere into a new threat. Researchers in May reported He said two coronaviruses have recombined in dogs in Indonesia. The result was a hybrid that infected eight children.
“A coronavirus that we’ve been watching for decades, which we thought was something our pets could take, could make a splash – we should have seen that coming, right?” said Carlson.
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