Predicting susceptibility to SARS‐CoV‐2 infection based on structural differences in ACE2 across species

Alexander, Matthew; Schoeder, Clara T.; Brown, Jacquelyn A.; Smart, Charles D; Moth, Chris; Wikswo, John P.; Capra, John A.; Meiler, Jens; Chen, Wenbiao; Madhur, Meena S

doi:10.1096/fj.202001808r

Cited by 48 publications

(48 citation statements)

References 68 publications

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“…Our study highlights the importance of banning illegal wildlife trade and consumption, and enforcing the importance of surveilling animals in close contact with humans as potential zoonotic reservoirs to prevent outbreaks in the future. studies have predicted ACE2 orthologs/SARS-CoV-2 S binding affinity or energies but lack of support by virus infection experimentation (16)(17)(18)(19)(20)(21). In this study, we experimentally assessed ACE2 orthologs from a broad range of species for their ability to support SARS-CoV-2 entry.…”

mentioning

confidence: 99%

Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2

Liu

Wang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

186

216

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The pandemic of COVID-19, caused by SARS-CoV-2, is a major global health threat. Epidemiological studies suggest that bats (Rhinolophus affinis) are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. By analyzing the conservation of five residues in two virus-binding hotspots of ACE2 (hotspot 31Lys and hotspot 353Lys), we predicted 80 ACE2 proteins from mammals that could potentially mediate SARS-CoV-2 entry. We chose 48 ACE2 orthologs among them for functional analysis, and showed that 44 of these orthologs—including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria—could bind the SARS-CoV-2 spike protein and support viral entry. In contrast, New World monkey ACE2 orthologs could not bind the SARS-CoV-2 spike protein and support viral entry. We further identified the genetic determinant of New World monkey ACE2 that restricts viral entry using genetic and functional analyses. These findings highlight a potentially broad host tropism of SARS-CoV-2 and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, underscoring the necessity to monitor susceptible hosts to prevent future outbreaks.

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mentioning

confidence: 99%

Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2

Liu

Wang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

186

216

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“…The ACE2-lentivirus system was used to introduce amino acid substitutions into mACE2 to identify the amino acids that are responsible for restricting SARS-CoV-2 replication in mACE2-expressing cells. Analysis of crystal structures and species susceptibilities has suggested residues that may be responsible for the differences in binding of the RBD to hACE2 and mACE2 (Alexander et al, 2020; Damas et al, 2020; Griffin et al, 2020; Rodrigues et al, 2020; Wang et al, 2020). Based on these in silico studies, we identified seven residues potentially responsible for the human-mouse differences.…”

Section: Resultsmentioning

confidence: 99%

ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

Rawle

Dumenil

et al. 2021

Preprint

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SARS-CoV-2 uses the human ACE2 receptor (hACE2), with mouse ACE2 (mACE2) unable to support infection. Herein we describe an ACE2-lentivirus system and illustrate its utility in vitro and in vivo. Transduction of non-permissive cell lines with hACE2 imparted replication competence, and transduction with mACE2 containing N30D, N31K, F83Y and H353K mutations, to match hACE2, rescued SARS-CoV-2 replication. hACE2-lentivirus transduction of C57BL/6J, IFNAR-/- and IL-28RA-/- mice lungs indicated type I and III IFN receptor knockout had minimal effect on virus replication. However, RNA-Seq illustrated that they were required for inflammatory responses in C57BL/6J mice, which were similar to those seen in COVID-19 patients. Finally, we illustrate the utility of hACE2 transduction for vaccine evaluation in C57BL/6J mice. The hACE2-lentivirus system thus has broad application in SARS-CoV-2 research, in particular allowing access to GM mice, while also offering the inherent advantages of lentiviral transduction such as stable genomic integration.

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“…It is known that wild-type mice are generally less susceptible to SARS-CoV-2 infections partly because murine ACE2 does not bind to SARS-CoV-2 as efficiently as hACE2. 22 Accordingly, transgenic mice overexpressing hACE2 in epithelial cells under the control of human cytokeratin 18 (K18) promoter, the K18-hACE2 mice, 23 have been generated and proven more susceptible to SARS-CoV-2 infection, manifested by more exaggerated lung inflammation and injury following intranasal virus inoculation. 23,24 Consistently, we found that lung ACE2 levels were elevated by 1-2 folds in K18-hACE2 mice as compared with gender-and age-matched wild-type C57BL/6 controls (Supporting Information Fig.…”

Section: Rbm-binding Mabs Also Specifically Blocked the Rbm-induced Gmentioning

confidence: 99%

Monoclonal antibodies capable of binding SARS-CoV-2 spike protein receptor-binding motif specifically prevent GM-CSF induction

Qiang

Zhu

et al. 2021

Journal of Leukocyte Biology

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A severe acute respiratory syndrome (SARS)-like coronavirus 2 (SARS-CoV-2) has recently caused a pandemic COVID-19 disease that infected approximately 94 million and killed more than 2,000,000 people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its envelope spike protein for binding the host angiotensin-converting enzyme 2 (ACE2) to gain viral entry. Currently, extensive efforts are being made to produce vaccines against a surface fragment of a SARS-CoV-2, such as the spike protein, in order to boost protective antibodies that can inhibit virus-ACE2 interaction to prevent viral entry. It was previously unknown how spike protein-targeting antibodies would affect innate inflammatory responses to SARS-CoV-2 infections. Here we generated a highly purified recombinant protein corresponding to the RBM of SARS-CoV-2, and used it to screen for cross-reactive monoclonal antibodies (mAbs). We found two RBM-binding mAbs that competitively inhibited its interaction with human ACE2, and specifically blocked the RBM-induced GM-CSF secretion in both human peripheral blood mononuclear cells and murine macrophage cultures. Our findings have suggested a possible strategy to prevent SARS-CoV-2-elicited "cytokine storm," and revealed a potentially anti-inflammatory and protective mechanism for SARS-CoV-2 spike-based vaccines.

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Predicting susceptibility to SARS‐CoV‐2 infection based on structural differences in ACE2 across species

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 48 publications

References 68 publications

Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2

Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2

ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

Monoclonal antibodies capable of binding SARS-CoV-2 spike protein receptor-binding motif specifically prevent GM-CSF induction

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