In the middle of 2020, a group of scientists Catching bats in Laotian caves Similar coronaviruses have been discovered that have wreaked havoc around the world.

Since then, some researchers have been studying one of these mysterious bat viruses in a high-security laboratory in Paris, hoping to find clues about how its cousin SARS-CoV-2 became a global threat. He killed one Approximately 15 million people.

Their work has borne fruit scientifically. Last year, scientists found that A bat virus has been infected. to human cells, at least in petri dishes. Last month, the team reported More reassuring news: the virus is not particularly harmful to laboratory animals. The findings suggest that SARS-CoV-2 spread rapidly and caused deadly disease after the two lineages diverged in the viral evolutionary tree.

If the Laotian virus jumps from bats to humans, the new study suggests, it may cause mild stomach upset rather than life-threatening pneumonia. Still, such laboratory experiments rekindle an old debate among scientists about the wisdom of using viruses closely related to known pathogens.

Proponents argue that this type of data is critical to understanding and preventing epidemics. For example, the new studies test whether bat viruses can modify the “furin cleavage site” characteristic of SARS-CoV-2 that allows it to efficiently infect human cells.

“Our motivation was to try to give some insight into the origin of Covid,” said Marc Eloit, a virologist at the Pasteur Institute in Paris.

But critics say scientists shouldn’t conduct experiments that make viruses better able to spread between humans, given the small but real chance these mutated pathogens could infect lab workers and escape into the outside world.

“To me, the benefits of this work outweigh the risks,” said Dr. David Relman, a microbiologist at Stanford University.

The bat virus at the center of Dr. Eloit’s experiment was discovered in 2011. During a summer 2020 expedition to limestone caves in northern Laos, a team of bats and French researchers captured bats flying from the caves and took saliva samples. Blood, urine and feces.

The scientists found five coronavirus genetic materials closely related to SARS-CoV-2. They found whole viruses, which they named BANAL-236, in feces from Marshall’s horseshoe bats (the virus refers to the bat’s rectal swab).

After the scientists returned to their labs, they found that BANAL-236 could infect human cells by binding tightly to the protein that SARS-CoV-2 uses to enter. In February, the researchers published these Findings In the journal Nature.

One last month Second wave of resultsHe examined the behavior of the virus in laboratory mice and monkeys, which is now being reviewed in the journal Science.

In one experiment, the scientists injected the virus into genetically engineered mice that are commonly used to study Covid. As it does in humans, SARS-CoV-2 multiplies rapidly in their lungs, causing them to lose weight and die.

BANAL-236, in contrast, struggled to infect the animal’s lungs, producing only about 1 percent of the virus produced by SARS-CoV-2 infection.

The researchers found that the virus was much easier to inject into the noses of two monkeys. BANAL-236 reproduces in their intestines rather than their lungs.

Dr. Eloit suspects that BANAL-236 is mild because it lacks a key feature essential to the success of SARS-CoV-2.

After a new SARS-CoV-2 virus forms in a cell, the spike proteins change shape, which has a spring-rainbow effect. When the virus binds to a new cell, the primed spike protein releases the molecular screws that attract it to the new host.

This shape-shifting region of the spike – known as the furin cleavage site – is critical to the success of SARS-CoV-2. When they have scientists Engineer For viruses lacking this site, the mutants struggle to replicate in the lungs of laboratory animals or to spread to new hosts.

Locating the furin cleavage site may be a critical step in SARS-CoV-2 evolution. To explore that possibility, Dr. Eloit and colleagues conducted laboratory experiments to allow BANAL-236 to develop new properties, such as a furin cleavage site.

The group is based on the study. Experiments Other scientists wait for bird flu viruses to enter chicken eggs and multiply. Then they transferred the new viruses to new eggs, and allowed them to reproduce again. With each transition, the virus had a chance to evolve. After 11 transfers, the scientists discovered that the flu viruses had evolved to become lethal to chickens.

Similarly, Pasteur’s researchers removed lung tissue from mice infected with BANAL-236 and used it to infect healthy animals. Then they passed the virus from mouse to mouse and repeated the cycle.

In another experiment, after treating human intestinal plates with BANAL-236, they used the new viruses produced by the cells to infect new foods.

But for both experiments, Dr. Eloit and his colleagues decided not to go up to 11 transfers, stopping at six.

“From a scientific point of view, we want to do more than six passages,” said Dr. Eloit. But we didn’t want to run the risk of adapting the bat virus to humans.

BANAL-236 did not locate the furin cleavage site in either assay. The virus got other mutations, but they didn’t make it any better at infecting mouse lungs.

Scientists have been conducting such evolutionary experiments – known as “sequential passage” – for more than a century. in fact, Vaccinations Many viruses, such as yellow fever, have been created by growing them in the laboratory: the viruses are modified in a petri dish into mild forms that cannot be injected into humans.

But in 2011 Controversy The safety of a series of transfection experiments was raised because they could generate new human pathogens. At the time, researchers were studying how influenza viruses, which cause intestinal infections in birds, could mutate into airborne forms to infect humans.

Two groups of researchers sprayed bird flu viruses into the noses of ferrets, waited for the viruses to replicate, and then transferred the new viruses to new ferrets. in near Viruses were created To be better to repeat in ferrets.

Some critics said the study was too reckless to be published, fearing that other researchers would copy the work and suddenly release a new pandemic flu strain. United States government It stopped Such attempts to develop a new policy to evaluate their safety.

Some studies have been restarted in recent years. But there is Stanford’s Dr. Relman and others. He filed a complaint The current rules are not clear enough.

A Pasteur Institute committee that reviews potentially dangerous biological studies has approved his team’s proposal to study the new bat viruses, Dr. Eloit said. The scientists conducted their experiments at the same level of safety as they did with the corona virus, known as biosafety level 3 or biosafety level 3. BSL-3.

Dr. Tom Inglesby, director of the Johns Hopkins Center for Health Security at the Bloomberg School of Public Health, said it was good for scientists to think about these potential risks. But he said he would like to see a clear reason to decide whether six passages are safe.

“It is impossible to predict whether these experiments will lead to more transmissible or more virulent viruses,” he said. “There is no hard and fast rule that six is ​​safe and no more.”

But Thomas Peacock, a virologist at Imperial College London, said he thought Dr Eloit and his colleagues were smart enough. In previous studies, the researchers found that antibodies produced by humans during Covid infections are very strong against BANAL-236, he said. That probably means the virus wouldn’t be able to spread much if it got out of the lab.

“This virus will probably hit a brick wall in the general population,” Dr. Peacock said. “I don’t have much of a problem with the tests.”

Other researchers agree with Dr. Eloit that the study is about how and when SARS-CoV-2 spreads to humans.

For Dr. Eloit, his team’s inability to produce a furin cleavage site on BANAL-236 in mouse or human intestinal cells suggests that the SARS-CoV-2 lineage acquired the furin site before it spread to humans. Once the virus enters another species of animal — sometimes called “intermediate hosts” — such as those sold in the U.S., it may not be easy for the virus to find its fury site, he said. Market Wuhan, China. “I don’t see any strong argument in favor of an intermediate host,” Dr. Eloit said.

But scientists who support the market situation see the new results in a different light. If the researchers were unable to induce BANAL-236 to change the position of furin during a series of passage experiments, some supporters of the “lab” thought that scientists in the Wuhan lab might be able to do it with SARS-CoV-2. leak” concept They proposed that

“This is another nail in the coffin of the lab leak theory,” said Edward Holmes, a virologist at the University of Sydney.

Dr. Peacock refused to draw strong conclusions from such small experiments. “I think it’s too difficult to ask to find Fury’s station after a few passages,” he said.

Dr. Eloit and colleagues are investigating the possibility that the ancestors of SARS-CoV-2 may have found the furin cleavage site while still in wild bats. The virus can be spread to an intermediate host or to people who are directly exposed to bats – such as those who collect bat guano, hunt or eat bats.

To test that idea, the scientists are working to get more samples from bats in Laos and neighboring countries. Dr. Eloit can’t say his hypothesis is more likely than others, but at least it’s something he can test.

“Our job as scientists is to investigate working hypotheses that we can test,” he said.



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