SARS-like coronaviruses in horseshoe bats (<i>Rhinolophus</i> spp.) in Russia, 2020

Alkhovsky, Sergey V.; Lenshin, Sergey; Av, Romashin; Vishnevskaya, Tatyana V.; Vyshemirsky, O. I.; Yi, Bulycheva; Dk, L'vov; Ak, Gitel'man

doi:10.1101/2021.05.17.444362

Cited by 7 publications

(14 citation statements)

References 23 publications

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“…Furthermore, replication in vivo is multifactorial [56] , and there are likely additional incompatibilities in immune antagonism and replication that may stifle a zoonotic event. For example, the Khosta viruses lack genes thought to antagonize the immune system, such as ORF8 [41] . While not sufficient, compatible interactions between viral entry proteins and host receptor proteins are likely necessary for zoonosis.…”

Section: Discussionmentioning

confidence: 99%

“…The RBDs from PDF-2370 and PDF-2386 were identical, and all three RBDs clustered closely with BtKY72 ( Fig 3B ), so we did not incorporate them into our study. In contrast, three highly unique RBDs were also discovered through ecological sequencing efforts; Khosta-1 and Khosta-2, observed in R. ferrumequinum and R. hipposideros bats in Sochi Russia [41] , and RhGB01 observed in a R. hipposideros bat in the United Kingdom [42] . We thus created SARS-CoV chimeric spikes encoding these RBDs.…”

Section: Multiple Clade 3 Sarbecoviruses Use Human and Rhinolophid Ace2mentioning

confidence: 99%

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Expanded ACE2 dependencies of diverse SARS-like coronavirus receptor binding domains

Roelle

Shukla

Pham

et al. 2021

Preprint

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Viral spillover from animal reservoirs can trigger public health crises and cripple the world economy. Knowing which viruses are primed for zoonotic transmission can focus surveillance efforts and mitigation strategies for future pandemics. Successful engagement of receptor protein orthologs is necessary during cross-species transmission. The clade 1 sarbecoviruses including SARS-CoV and SARS-CoV-2 enter cells via engagement of ACE2, while the receptor for clade 2 and clade 3 remains largely uncharacterized. We developed a mixed cell pseudotyped virus infection assay to determine whether various clade 2 and 3 sarbecovirus spike proteins can enter HEK 293T cells expressing human or Rhinolophus horseshoe bat ACE2 proteins. The receptor binding domains from BtKY72 and Khosta-2 used human ACE2 for entry, while BtKY72 and Khosta-1 exhibited widespread use of diverse rhinolophid ACE2s. A lysine at ACE2 position 31 appeared to be a major determinant of the inability of these RBDs to use a certain ACE2 sequence. The ACE2 protein from R. alcyone engaged all known clade 3 and clade 1 receptor binding domains. We observed little use of Rhinolophus ACE2 orthologs by the clade 2 viruses, supporting the likely use of a separate, unknown receptor. Our results suggest that clade 3 sarbecoviruses from Africa and Europe use Rhinolophus ACE2 for entry, and their spike proteins appear primed to contribute to zoonosis under the right conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Multiple Clade 3 Sarbecoviruses Use Human and Rhinolophid Ace2mentioning

confidence: 99%

Expanded ACE2 dependencies of diverse SARS-like coronavirus receptor binding domains

Roelle

Shukla

Pham

et al. 2021

Preprint

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“…Unfortunately, new SARS-2 variants of concern (VOCs), including the heavily mutated Omicron VOCs (2)(3)(4)(5)(6)(7), may prolong the COVID-19 pandemic. In addition, the discovery of diverse sarbecoviruses in bats, some of which bind the SARS-1 and SARS-2 entry receptor, angiotensin-converting enzyme 2 (ACE2) (8)(9)(10)(11)(12)(13)(14), raises the possibility of another coronavirus pandemic. Hence there is an urgent need to develop vaccines and therapeutics to protect against both SARS-2 VOCs and zoonotic sarbecoviruses.…”

mentioning

confidence: 99%

Mosaic RBD nanoparticles protect against multiple sarbecovirus challenges in animal models

Cohen

Doremalen

Greaney

et al. 2022

Preprint

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To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

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“…ACE2 orthologs of bats found in Africa, though the full range of non-Asian bat species that harbor sarbecoviruses and their ACE2 sequences are underexplored [14][15][16]33 .…”

mentioning

confidence: 99%

ACE2 binding is an ancestral and evolvable trait of sarbecoviruses

Starr

Zepeda

Walls

et al. 2021

Preprint

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Two different sarbecoviruses have caused major human outbreaks in the last two decades. Both these sarbecoviruses, SARS-CoV-1 and SARS-CoV-2, engage ACE2 via the spike receptor-binding domain (RBD). However, binding to ACE2 orthologs from humans, bats, and other species has been observed only sporadically among the broader diversity of bat sarbecoviruses. Here, we use high-throughput assays to trace the evolutionary history of ACE2 binding across a diverse range of sarbecoviruses and ACE2 orthologs. We find that ACE2 binding is an ancestral trait of sarbecovirus RBDs that has subsequently been lost in some clades. Furthermore, we demonstrate for the first time that bat sarbecoviruses from outside Asia can bind ACE2. In addition, ACE2 binding is highly evolvable: for many sarbecovirus RBDs there are single amino-acid mutations that enable binding to new ACE2 orthologs. However, the effects of individual mutations can differ markedly between viruses, as illustrated by the N501Y mutation which enhances human ACE2 binding affinity within several SARS-CoV-2 variants of concern but severely dampens it for SARS-CoV-1. Our results point to the deep ancestral origin and evolutionary plasticity of ACE2 binding, broadening consideration of the range of sarbecoviruses with spillover potential.

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SARS-like coronaviruses in horseshoe bats (Rhinolophus spp.) in Russia, 2020

Cited by 7 publications

References 23 publications

Expanded ACE2 dependencies of diverse SARS-like coronavirus receptor binding domains

Expanded ACE2 dependencies of diverse SARS-like coronavirus receptor binding domains

Mosaic RBD nanoparticles protect against multiple sarbecovirus challenges in animal models

ACE2 binding is an ancestral and evolvable trait of sarbecoviruses

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