Sequence determinants of human-cell entry identified in ACE2-independent bat sarbecoviruses: A combined laboratory and computational network science approach

Khaledian, Mohsen; Ulusan, Sinem; Erickson, Jeffery A.; Fawcett, Stephen; Letko, Michael; Broschat, Shira L.

doi:10.1016/j.ebiom.2022.103990

Cited by 22 publications

(39 citation statements)

References 34 publications

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“…We have previously shown that a small number of clade 2 RBDs, such as As6526 and Rs4081, also exhibit protease-mediated, ACE2-independent entry, and similar phenotypes have been described for other bat coronaviruses [ 1 , 35 ]. Analogous to Khosta 1, the completely ACE2-independent RBD clade 2 sarbecovirus, Rs4081, also efficiently infects Huh-7 cells in the presence of trypsin [ 36 ]. Because not all of the RBD clade 2 and 3 sarbecoviruses exhibit trypsin-dependent entry in our comparative assays with chimeric spikes, these findings collectively suggest that some coronaviruses may infect human cells through a presently unknown receptor.…”

Section: Discussionmentioning

confidence: 99%

An ACE2-dependent Sarbecovirus in Russian bats is resistant to SARS-CoV-2 vaccines

et al. 2022

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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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Section: Discussionmentioning

confidence: 99%

An ACE2-dependent Sarbecovirus in Russian bats is resistant to SARS-CoV-2 vaccines

et al. 2022

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“…In addition, the spike protein of some bat coronaviruses including isolates RaTG13 and RmYN02 were shown to be unable to bind cognate bat ACE2 receptors (27,28), suggesting that compatibility between spike and receptor may not be necessary for virus maintenance in bats. The ability to bind human ACE2 has been mapped to residues within the RBD that are deleted or mutated in the majority of bat coronaviruses (26,(29)(30)(31). Furthermore, receptor-independent entry of coronaviruses has been described for murine hepatitis virus (32), MERS-CoV (33), and SARS-CoV-2 (34).…”

Section: Discussionmentioning

confidence: 99%

Spike-independent infection of human coronavirus 229E in bat cells

Linster

Mah

Low

et al. 2021

Preprint

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Bats are a likely zoonotic reservoir for a range of human pathogens including endemic human coronaviruses and SARS-CoV-2. Despite the high burden caused by these viruses, the factors required for the establishment and ongoing transmission in humans are not well understood, hampering efforts for pandemic preparedness. To help understand those adaptations required to cross the species barrier, we serially passaged endemic human coronavirus 229E isolates in a newly established Rhinolophus (horseshoe bat) kidney cell line. Here we report extensive mutations, including deletions, in the virus genome that result in the loss of spike protein expression, while maintaining the capability to infect bat cells. While we observed a loss of infectivity of human cells for all viruses with spike deletions, one isolate (2613) with an insertion that results in an early stop codon, was recovered from human cells. Deep sequencing of isolate 2613 showed that the majority population had acquired additional nucleotide insertions in the spike resulting in an additional codon that restores spike function. Spike-independent replication of coronaviruses provides an alternative route for infection of host species that don't share common cell-entry receptors.

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“…Previously, we showed that viral-like particles pseudotyped with S from some of the clade 2 viruses could infect human cells in the presence of trypsin, demonstrating that clade 2 viruses may also pose a risk of cross-species transmission ( 19 , 20 ). Although viral pseudotypes are generally a suitable model of true viral cell entry, there have been discrepancies between pseudotype and viral replication results for other bat sarbecoviruses.…”

Section: Introductionmentioning

confidence: 98%

“…While clade 2 viruses were the first sarbecoviruses discovered in bats, initial attempts to isolate these viruses from field samples or propagate clade 2 viruses from reverse genetics systems were unsuccessful ( 1 , 6 , 10 , 19 , 21 ). To date, viruses from clades 2, 3, and 4 have only been assessed by protein-protein binding assays (measuring affinity of purified spike protein fragments for purified receptor binding fragments) or pseudotyped systems due to lack of live virus growth ( 15 , 19 to 21 ).…”

Section: Introductionmentioning

confidence: 99%

ACE2-Independent Bat Sarbecovirus Entry and Replication in Human and Bat Cells

Guo

Dong

et al. 2022

mBio

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Our studies demonstrate that some unexplored sarbecoviruses are capable of replicating in human and bat cells in an ACE2-independent way but need a high trypsin environment. We found that trypsin is not compensated by other known proteases involved in some coronavirus entry. This work provides important information that the trypsin-dependent entry may be a widely employed mechanism for coronaviruses and will help for further understanding the biological features of the less-studied viruses.

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Sequence determinants of human-cell entry identified in ACE2-independent bat sarbecoviruses: A combined laboratory and computational network science approach

Cited by 22 publications

References 34 publications

An ACE2-dependent Sarbecovirus in Russian bats is resistant to SARS-CoV-2 vaccines

An ACE2-dependent Sarbecovirus in Russian bats is resistant to SARS-CoV-2 vaccines

Spike-independent infection of human coronavirus 229E in bat cells

ACE2-Independent Bat Sarbecovirus Entry and Replication in Human and Bat Cells

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