NIH-halted study unveils its massive analysis of bat coronaviruses

An international team of scientists whose funding for research on bat coronaviruses was recently yanked by the U.S. government has published what it calls the most comprehensive analysis ever done of such viruses. In a preprint posted yesterday on bioRxiv, the researchers examine partial genetic sequences of 781 coronaviruses found in bats in China, more than one-third of which have never been published.

Although the analysis cannot pinpoint the origin of SARS-CoV-2, the virus that causes COVID-19, it does single out one genus, Rhinolophus, also known as Chinese horseshoe bats, as crucial to the evolution of coronaviruses. “It seems that by sheer phylogeographic, historical, evolutionary bad luck, Rhinolophus ends up being the major reservoir for SARS [severe acute respiratory syndrome]-related coronaviruses,” says study co-author Peter Daszak, president of EcoHealth Alliance, a nonprofit that last month saw its multimillion-dollar grant to study bat coronaviruses with colleagues in China cut by the U.S. National Institutes of Health (NIH). On 21 May, 77 Nobel laureates urged NIH to reconsider its decision to end the funding.

Another co-author on the study is Shi Zheng-Li, the bat researcher at the Wuhan Institute of Virology who has received much scrutiny because of allegations by President Donald Trump and others—unsupported by any direct evidence to date—that the COVID-19 pandemic originated in her lab. Shi has strongly denied the suggestion that her lab ever handled a bat virus closely related to SARS-CoV-2.

Between 2010 and 2015, Shi, Daszak, and their collaborators captured hundreds of bats in numerous Chinese provinces and took oral and rectal swabs from them. They also placed tarps under bat colonies to collect the animals’ feces. They extracted RNA from these samples and used standard lab techniques to amplify and sequence a short piece of the genome that is common to all coronaviruses but varies enough to distinguish them. This allowed the scientists to essentially build a family tree of bat coronaviruses and examine which bat genus carried the greatest diversity of the viruses. They found a Rhinolophus coronavirus that was 96.2% identical in sequence to SARS-CoV-2, the closest relative yet found, but calculations suggest it would take decades for that bat virus to mutate into the new human pathogen.

The leading theory for the origin of SARS-CoV-2 is that a bat virus long ago jumped into another species, where it then mutated into a variant that later infected humans. The new study, although “very useful,” doesn’t clarify this scenario, says Edward Holmes, an evolutionary biologist at the University of Sydney who has studied the genetics of bat coronaviruses and co-authored the paper that first revealed the sequence of SARS-CoV-2. But the paper does demonstrate a “huge diversity” of bat coronaviruses in China that potentially can jump between species, Holmes says.

Looking for coronaviruses outside of bats may still be key to the origin mystery. “While bats are clearly major hosts for coronaviruses, until we have a wider sampling of wildlife species we will not be able to fully resolve the evolutionary events involved in the genesis of SARS-CoV-2, particularly whether it jumped straight from bats to humans or went through an intermediate host,” Holmes says.

Daszak agrees that more animal species need to be sampled. He points to evidence of closely related coronaviruses in pangolins. (Eight coronavirus sequences from pangolins are included in the analysis.) “I think the pangolin story has a lesson for us: Don’t get stuck in a box thinking that this is all about bats” Daszak says, although he stresses that he does not think existing data make a compelling case for SARS-CoV-2 having entered humans via pangolins. Sampling, he says, also needs to extend to neighboring countries Laos, Vietnam, and Myanmar. “That’s a well-known biogeographic region that’s got a high diversity of bats and clearly has a high diversity of SARS-related coronaviruses.”

Recent coronavirus outbreaks in humans—SARS, Middle East respiratory syndrome, and SARS-CoV-2—have been caused by a group known as beta-coronaviruses. But the new analysis suggests alpha-coronaviruses may actually be better at jumping species barriers—and could also lead to epidemics in humans or animals. “Future work discovering and characterizing the biological properties of bat alpha-coronaviruses may therefore be of potential value for public and livestock health,” Daszak and his colleagues write.

Duke University’s Feng Gao, who led an analysis published on 29 May in Science Advances about the evolution of SARS-CoV-2, says the new work by Daszak, Shi, and colleagues underscores that researchers have just sampled “the tip of the iceberg” of the coronaviruses circulating between bats that could jump into humans and other species. “We really have to survey the wild population better,” Gao says.

One “pretty big limitation” of EcoHealth-led study, Gao notes, is that the researchers cataloged the bat viruses by a tiny part of their genetic material. The entire genome of bat coronaviruses consists of about 30,000 RNA bases, but obtaining full sequences is often difficult and expensive. So instead the research team sequenced just 440 bases from the gene that codes for a key viral enzyme, the RNA-dependent RNA polymerase. Gao says getting full viral sequences would have provided much more biological information on the different viruses found.

Daszak says that was going to be the next step but then NIH cut the grant. “We were planning to get full genome sequences from these samples and find out which [viruses] are likely able to bind to human cell surface receptors,” he says. “We won’t be able to do that work without the funding, unfortunately.” And even the hundreds of viruses included in the current paper are only a fraction of what remains to be discovered, Daszak says. “We are looking at maybe 10,000 to 15,000 bat coronaviruses that are out there.”

There is plenty of evidence that some of these viruses are spilling over to humans all the time in southern China, Daszak says. In an earlier paper, Daszak and co-workers found SARS-related antibodies to coronaviruses in about 3% of people they sampled in China living near bat caves, suggesting they had been infected by some of these viruses. He argues that the world needs to change its approach and go from reacting to pandemics to trying to identify dangerous coronaviruses before they emerge. Many more viruses that are closely related to SARS-CoV-2 are just waiting to be discovered in wildlife, Daszak says. “But, of course, if history repeats itself, by the time we’ve found all the rest of the SARS-2 clade, something else will be emerging.”

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