Identification of a novel lineage bat SARS-related coronaviruses that use bat ACE2 receptor

Abstract

Severe respiratory disease coronavirus-2 (SARS-CoV-2) has been the most devastating disease COVID-19 in the century. One of the unsolved scientific questions of SARS-CoV-2 is the animal origin of this virus. Bats and pangolins are recognized as the most probable reservoir hosts that harbor highly similar SARS-CoV-2 related viruses (SARSr-CoV-2). This study identified a novel lineage of SARSr-CoVs, including RaTG15 and seven other viruses, from bats at the same location where we found RaTG13 in 2015. Although RaTG15 and the related viruses share 97.2% amino acid sequence identities with SARS-CoV-2 in the conserved ORF1b region, it only shows less than 77.6% nucleotide identity to all known SARSr-CoVs at the genome level, thus forming a distinct lineage in the Sarbecovirus phylogenetic tree. We found that the RaTG15 receptor-binding domain (RBD) can bind to ACE2 from Rhinolophus affinis, Malayan pangolin, and use it as an entry receptor, except for ACE2 from humans. However, it contains a short deletion and has different key residues responsible for ACE2 binding. In addition, we showed that none of the known viruses in bat SARSr-CoV-2 lineage discovered uses human ACE2 as efficiently as the pangolin-derived SARSr-CoV-2 or some viruses in the SARSr-CoV-1 lineage. Therefore, further systematic and longitudinal studies in bats are needed to prevent future spillover events caused by SARSr-CoVs or to understand the origin of SARS-CoV-2 better.

Variation in synonymous nucleotide composition among genomes of sarbecoviruses and consequences for the origin of COVID-19

“…The YunSar genomes are divergent from other Sarbecovirus genomes (between 23% and 27%) and their SNC revealed extremes values for many variables (2/12 in Table 2; 12/32 in Table 3; 19/59 in Table 4). More recently, eight YunSar viruses showing 98% of genomic identity with RmYN05 and RstYN04 have been described from Rhinolophus affinis and Rhinolophus stheno collected in May 2015 in Mojiang County, Yunnan province (Guo et al 2021). Although current data indicate that the YunSar group is endemic to Yunnan, many regions should be explored to better characterise its geographic distribution, including North East India, nothern Myanmar, nothern Laos and nothern Vietnam.…”

The high diversity of SARS-CoV-2-related coronaviruses in pangolins alters potential ecological risks

“…Both the pangolin-CoV-GDC and pangolin-CoV-GXC viruses were isolated from M. javanica (Malayan pangolin) in previous studies, and our results demonstrate for the first time that pangolin-CoV is also present in M. pentadactyla , suggesting that pangolin-CoVs have a relatively complex evolutionary history that deserves further study. It should be noted that both pangolin-CoV-GXC and pangolin-CoV-GDC had entry efficiencies into cells expressing the human ACE2 receptor comparable to those of SARS-CoV-2 pseudoviruses ( Dicken et al, 2021 ; Guo et al, 2021 ; Nie et al, 2021 ; Niu et al, 2021 ; Zhang et al, 2021 ). Together, the observation of multiple recombination events during the evolution of SARS-CoV-2 ( Boni et al, 2020 ; Gryseels et al, 2021 ; Zhou & Shi 2021 ), the high genetic diversity of pangolin-CoVs in Southeast Asia and neighboring regions, and the overlapping distributions of the pangolin-CoVs, bat-CoVs, and other coronaviruses ( Lacroix et al, 2017 ; Latinne et al, 2020 ), highlight the ecological risk of zoonotic transmission of novel pathogenic SC2r-CoVs.…”

“…Currently, M. javanica is the only known pangolin species that harbors coronaviruses closely related to SARS-CoV-2. Although the pangolin-CoVs tend to be more distantly related to SARS-CoV-2 than the aforementioned bat-derived SC2r-CoVs, recent studies show that the receptor-binding domain (RBD) of both pangolin-CoV sublineages can potentially bind the human ACE2 receptor ( Dicken et al, 2021 ; Guo et al, 2021 ; Nie et al, 2021 ; Niu et al, 2021 ; Zhang et al, 2021 ), raising concerns about the potential risks of spillover of these pangolin-CoVs to humans.…”

COVID-19 is a natural infectious disease

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