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SARS-CoV-2-Related Coronaviruses From Bats in Laotian Caves Can Infect Human Cells

Rhinolophus trifoliatus bat

NEW YORK – A team led by researchers at the University of Paris has identified SARS-CoV-2-related viruses in bats in Laos that are capable of entering human cells by binding to the ACE2 receptor, supporting the notion that the COVID-19-causing virus may have emerged from an animal reservoir in Asia.

"The animal reservoir of SARS-CoV-2 is unknown despite reports of various SARS-CoV-2-related viruses in Asian Rhinolophus bats, including the closest virus from R. affinis, RaTG13, and in pangolins," senior author Marc Eloit, a researcher at the Pasteur Institute and the University of Paris, and his colleagues explained in a paper published in Nature on Wednesday, adding that SARS-CoV-2 progenitor bat viruses that are able to enter human cells through a human ACE2 pathway had previously not been identified.

With that in mind, the researchers used a nested PCR screening approach to look for coronavirus sequences in 247 blood, 608 saliva, 539 anal/fecal, and 157 urine swab samples from 645 bats caught at limestone caves at four sites in the Oudomxay province in northern Laos from the summer of 2020 to early 2021. The bats spanned 46 species and half a dozen bat families, they noted, and coronavirus sequences turned up in 24 representatives from 10 bat species.

When the team compared these amplicons to viral database sequences, it tracked down sequences that lined up with several known alphacoronaviruses or betacoronaviruses, along with sequences falling in the same sarbecovirus subgenus that contains SARS-CoV and SARS-CoV-2.

With whole-genome sequencing and phylogenetic analyses focused on five of the sarbecoviruses, the researchers uncovered close genetic relationships between SARS-CoV-2 and three of the viruses found in insectivorous Rhinolophus bat species in Laos. Recombination breakpoint analysis provided clues to the mosaicism detected in SARS-CoV-2 and similar viruses.

Through a series of follow-up protein crystal structure and cell line experiments, meanwhile, the researchers demonstrated that viruses distinct from SARS-CoV-2 at one or two amino acid residues in the receptor-binding domain of the spike protein could enter human cells via the ACE2 protein and replicate in them — processes that were curbed by the addition of SARS-CoV-2 neutralizing antibodies.

"[O]ur results pinpoint the presence of new bat sarbecoviruses that seem to have the same potential for infecting humans as early strains of SARS-CoV-2," the authors wrote, adding that these and other findings "support the hypothesis that SARS-CoV-2 could originally result from a recombination of sequences pre-existing in Rhinolophus bats living in the extensive limestone cave systems of South-East Asia and South China."

The newly-detected sarbecoviruses appeared to be as good or better at binding the ACE2 receptor protein than the SARS-CoV-2 strain initially identified in Wuhan, China, the team noted, though they are all missing a furin cleavage binding site found in the SARS-CoV-2 RBD.

Another study published in Nature by researchers at the University of Texas Medical Branch and their colleagues in early 2021 demonstrated that a version of SARS-CoV-2 missing the furin site could replicate in hamster and transgenic mouse models but appeared to protect these animals against severe disease when they were later exposed to wild-type versions of SARS-CoV-2.

"Guano collectors, or certain ascetic religious communities who spend time in or very close to caves, as well as tourists visiting caves, are particularly at risk of being exposed," the authors noted. "Further investigations are needed to assess if such exposed populations have been infected, symptomatically or not, by one of these viruses, and whether infection could confer protection against subsequent SARS-CoV-2 infections."