Emily
Editor, Senior Moderator
https://journals.plos.org/plospathog...l.ppat.1010828
Seifert SN, Bai S, Fawcett S, Norton EB, Zwezdaryk KJ, Robinson J, et al. (2022) An ACE2-dependent Sarbecovirus in Russian bats is resistant to SARS-CoV-2 vaccines. PLoS Pathog 18(9): e1010828. https://doi.org/10.1371/journal.ppat.1010828
Abstract
Spillover of sarbecoviruses from animals to humans has resulted in outbreaks of severe acute respiratory syndrome SARS-CoVs and the ongoing COVID-19 pandemic. Efforts to identify the origins of SARS-CoV-1 and -2 has resulted in the discovery of numerous animal sarbecoviruses–the majority of which are only distantly related to known human pathogens and do not infect human cells. The receptor binding domain (RBD) on sarbecoviruses engages receptor molecules on the host cell and mediates cell invasion. Here, we tested the receptor tropism and serological cross reactivity for RBDs from two sarbecoviruses found in Russian horseshoe bats. While these two viruses are in a viral lineage distinct from SARS-CoV-1 and -2, the RBD from one virus, Khosta 2, was capable of using human ACE2 to facilitate cell entry. Viral pseudotypes with a recombinant, SARS-CoV-2 spike encoding for the Khosta 2 RBD were resistant to both SARS-CoV-2 monoclonal antibodies and serum from individuals vaccinated for SARS-CoV-2. Our findings further demonstrate that sarbecoviruses circulating in wildlife outside of Asia also pose a threat to global health and ongoing vaccine campaigns against SARS-CoV-2
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Khosta virus receptor binding domains are distinct from human viruses
Khosta-1 and -2 were identified by Alkhovsky and colleagues in bat samples collected between March-October 2020 near Sochi National Park [12]. Phylogenetic analysis of the conserved viral gene, Orf1ab, revealed these viruses were most closely related to another sarbecovirus found in Bulgaria in 2008 (known as BM48-31 or Bg08), and form a lineage sarbecoviruses distinct from human pathogens, SARS-CoV-1 and -2 [12]. A list of viruses and accession numbers used in this study can be found in Table 1. Phylogenetic analysis of the spike RBD further reflected the close relatedness between Khosta -1 and -2 with BM48-31 and other clade 3 RBD viruses we have previously tested from Uganda and Rwanda [1,13] (Fig 1A). Clade 3 RBDs, including the Khosta viruses, contain a truncated surface-exposed loop, as compared to the ACE2-dependent, clade 1 viruses such as SARS-CoV, and additionally vary in many of the residues known for clade 1 viruses to interact with human ACE2 [1,2,13,14].
...
Our findings with chimeric, SARS-CoV-2 spike show that just replacing the RBD is sufficient to reduce efficacy of SARS-CoV-2 spike-directed vaccines (Fig 4). However, sarbecovirus recombination in nature typically occurs via template switching resulting in acquisition of regions larger than the NTD [42]. Thus, a naturally recombinant virus with Khosta 2 may actually acquire more Khosta 2 spike, which as we show here with full protein, is also infectious against human cells and ACE2 (Fig 3). Taken together, our findings with the Khosta viruses underscore the urgent need to develop broader-protecting universal Sarbecovirus vaccines.
Seifert SN, Bai S, Fawcett S, Norton EB, Zwezdaryk KJ, Robinson J, et al. (2022) An ACE2-dependent Sarbecovirus in Russian bats is resistant to SARS-CoV-2 vaccines. PLoS Pathog 18(9): e1010828. https://doi.org/10.1371/journal.ppat.1010828
Abstract
Spillover of sarbecoviruses from animals to humans has resulted in outbreaks of severe acute respiratory syndrome SARS-CoVs and the ongoing COVID-19 pandemic. Efforts to identify the origins of SARS-CoV-1 and -2 has resulted in the discovery of numerous animal sarbecoviruses–the majority of which are only distantly related to known human pathogens and do not infect human cells. The receptor binding domain (RBD) on sarbecoviruses engages receptor molecules on the host cell and mediates cell invasion. Here, we tested the receptor tropism and serological cross reactivity for RBDs from two sarbecoviruses found in Russian horseshoe bats. While these two viruses are in a viral lineage distinct from SARS-CoV-1 and -2, the RBD from one virus, Khosta 2, was capable of using human ACE2 to facilitate cell entry. Viral pseudotypes with a recombinant, SARS-CoV-2 spike encoding for the Khosta 2 RBD were resistant to both SARS-CoV-2 monoclonal antibodies and serum from individuals vaccinated for SARS-CoV-2. Our findings further demonstrate that sarbecoviruses circulating in wildlife outside of Asia also pose a threat to global health and ongoing vaccine campaigns against SARS-CoV-2
...
Khosta virus receptor binding domains are distinct from human viruses
Khosta-1 and -2 were identified by Alkhovsky and colleagues in bat samples collected between March-October 2020 near Sochi National Park [12]. Phylogenetic analysis of the conserved viral gene, Orf1ab, revealed these viruses were most closely related to another sarbecovirus found in Bulgaria in 2008 (known as BM48-31 or Bg08), and form a lineage sarbecoviruses distinct from human pathogens, SARS-CoV-1 and -2 [12]. A list of viruses and accession numbers used in this study can be found in Table 1. Phylogenetic analysis of the spike RBD further reflected the close relatedness between Khosta -1 and -2 with BM48-31 and other clade 3 RBD viruses we have previously tested from Uganda and Rwanda [1,13] (Fig 1A). Clade 3 RBDs, including the Khosta viruses, contain a truncated surface-exposed loop, as compared to the ACE2-dependent, clade 1 viruses such as SARS-CoV, and additionally vary in many of the residues known for clade 1 viruses to interact with human ACE2 [1,2,13,14].
...
Our findings with chimeric, SARS-CoV-2 spike show that just replacing the RBD is sufficient to reduce efficacy of SARS-CoV-2 spike-directed vaccines (Fig 4). However, sarbecovirus recombination in nature typically occurs via template switching resulting in acquisition of regions larger than the NTD [42]. Thus, a naturally recombinant virus with Khosta 2 may actually acquire more Khosta 2 spike, which as we show here with full protein, is also infectious against human cells and ACE2 (Fig 3). Taken together, our findings with the Khosta viruses underscore the urgent need to develop broader-protecting universal Sarbecovirus vaccines.