Researchers at the Pasteur Institute have isolated bat viruses that are extremely similar to the SARS-CoV-2 coronavirus that caused the Covid-19 pandemic. These viruses could be the missing link that explains the transition to humans. This discovery reinforces the hypothesis of a natural origin of SARS-CoV-2, but also shows that this type of dangerous virus is much more widespread in nature than previously thought.
In February 2020, Chinese researchers discovered in Yunnan bats a strain of coronavirus called RaTG13, which is 96.2% identical to SARS-CoV-2, the virus that caused the current pandemic. In November, researchers at the Pasteur Institute in France isolated three coronaviruses from bats in Laos that showed strong similarities to SARS-CoV-2. A new analysis published in the journal Nature confirmed this finding: the three strains, named Banal-52, Banal-103, and Banal-236, share 95% of their genome with SARS-CoV-2, and one of them, Banal-52, is even 96.8% similar, i.e. the closest relative of SARS-CoV-2 ever identified. “This strengthens the hypothesis that SARS-CoV-2 has a natural origin, but also raises concerns that there are many coronaviruses in nature that could infect humans,” Nature reports.
Bat viruses may bind to a human receptor for the first time
Until now, none of the viruses discovered in bats had sufficient characteristics to explain their transmission to humans. One of the keys to this infection lies in the sequence encoding the spike protein on the surface of SARS-CoV-2. This sequence, called the RBD (receptor binding domain), is critical because it determines the binding affinity of the virus to the ACE2 receptor, which is present in human cells and acts as a gateway for the virus.
Despite the similarities, RaTG13 shows a low affinity for the RBD sequence of SARS-CoV-2, with only 11 of the 17 amino acids being identical. Therefore, the infectivity of RaTG13 is limited. “No virus close to SARS-CoV-2 uses ACE2 to invade human cells,” say the authors of the (as yet unpublished) paper published on Research Square. On the other hand, SARS-CoV-2 does not infect bats or animal cells tested so far. In short, there’s a missing piece of the puzzle to explain the virus’s passage to humans, leading some to believe that it was a laboratory leak.
However, the three viruses collected from saliva, feces, and urine samples from 645 bats in caves in northern Laos appear to be able to bind to the known ACE2 receptor. Banal-52’s RBD, for example, differs by a single nucleotide from that of SARS-CoV-2, and Banal-236 shares 15 of the 17 nucleotides of its RBD. The researchers also conducted laboratory tests that confirmed Banal-236’s ability to bind to the ACE2 receptor and infect human cells.
However, there are still some missing links to explain the passage of the virus to humans. All coronaviruses discovered so far lack a special sequence, the furin cleavage site (present on the SARS-CoV-2 genome), which plays an important role in the fusion between the viral and cell membranes and is associated with increased pathogenicity in humans. Another unanswered question: the study does not indicate how these viruses discovered in Laos could have reached Wuhan in central China, where the Covid-19 pandemic began. In fact, a previous study sampled 13,000 bats between 2016 and 2021 in China, and researchers found no close relatives of SARS-CoV-2, concluded that they are “extremely rare” in China.
Chinese caves, an ideal ecosystem for the emergence of dangerous viruses
Ultimately, the most likely hypothesis is that of recombination between different bat coronaviruses, whose genetic sequences have mixed together to produce a strain that is particularly dangerous to humans. “SARS-CoV-2 could be the result of a recombination of pre-existing sequences in Rhinolophus bats living in the vast limestone caves of Southeast Asia and southern China, which provide ideal conditions for species interaction,” said the Institut Pasteur researchers.