Horseshoe bats from Southeast Asia host a high diversity of Sarbecoviruses, including close ancestors of SARS-CoV-2
Résumé
Background:
Bats are a major reservoir for zoonotic viruses, including coronaviruses. Since the emergence of SARS-CoV, considerable efforts have been directed towards describing the diversity of Coronaviridae circulating in bats, leading to the discovery of several precursors of both epidemic and pandemic coronaviruses. More recently, the emergence of SARS-CoV-2 has underscored the importance of monitoring the circulation of sarbecoviruses associated with horseshoe bats, particularly in Southeast Asia, which stands out by one of the highest diversities of bat species globally.
Methods:
We investigated the circulation of sarbecoviruses in horseshoe bats from Laos and Vietnam, collecting urine, blood, oral and rectal swabs from more than 850 insectivorous bats living in the karstic ecosystem at the border of China, Laos and Vietnam.
Results:
We discovered 19 sarbecoviruses in Rhinolophus marshalli, R. malayanus, R. pusillus, R. thomasi, R. siamensis and R. coelophyllus. Phylogenetic analyses revealed recombination and cross-species transmission between sympatric bat species as major drivers of virus evolution. The host range and tropism of bat sarbecoviruses are partly driven by the ability of the viral spike protein to interact with the cellular ACE2 receptor. We identified various interaction patterns that shed light on the risk of cross-species transmission of bat sarbecoviruses to humans. Notably, Vietnamese sarbecoviruses do not appear to interact with human ACE2 while Laotian sarbecoviruses do, with a higher affinity than the initial strain of SARS-CoV-2. Importantly, none of these sarbecoviruses harbor a furin cleavage site, indicating that the enteric tropism of these viruses in bats does not require such site. Then, we studied the pathogenicity of BANAL-236 virus (a Laotian R. marshalli sarbecovirus) in human-relevant animal models. We demonstrated that this bat sarbecovirus efficiently replicates in enteric tissues, does not cause major symptoms in humanized mice and macaques; and that serial passages on intestinal cells or humanized mice do not select for viral populations harboring the furin site, nor alter the tropism and virulence of the new strain. This enterotropism may account for the lack of serological detection of past infection by bat sarbecoviruses of human populations highly exposed to bat guano. This suggests that bat/human spillover infections of sarbecoviruses, if they occur, are rare; and that the acquisition of a furin site was not selected through a clinically silent circulation of bat sarbecoviruses in humans. The acquisition of such cleavage site through recombination from a donor organism remains hypothetical regarding the origin of the donor sequences, the host harboring this recombination event and its positive selection.
Conclusion:
Understanding the eco-epidemiology of bat sarbecoviruses will not only help deciphering the origin of SARS-CoV-2 and the way it emerged from its bat reservoir to humans, but it will allow to mitigate the risk of emergence of novel bat-associated sarbecoviruses.
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