Literature detail

The SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins.

Carina Conceicao¹ Nazia Thakur¹ Stacey Human¹ James T Kelly¹ Leanne Logan¹ Dagmara Bialy¹ Sushant Bhat¹ Phoebe Stevenson-Leggett¹ Adrian K Zagrajek¹ Philippa Hollinghurst^1,2 Michal Varga¹ Christina Tsirigoti¹ Matthew Tully¹ Chris Chiu¹ Katy Moffat¹ Adrian Paul Silesian¹ John A Hammond¹ Helena J Maier¹ Erica Bickerton¹ Holly Shelton¹ Isabelle Dietrich¹ Stephen C Graham³ Dalan Bailey¹

Affiliations 3 institutions

The Pirbright Institute, Woking, Surrey, United Kingdom.
Department of Microbial Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
Department of Pathology, University of Cambridge, Cambridge, United Kingdom.

PMID 33347434 2020 PLoS Biol eng epublish

PubMed DOI Browse context

Article

Publication summary

SARS Coronavirus 2 (SARS-CoV-2) emerged in late 2019, leading to the Coronavirus Disease 2019 (COVID-19) pandemic that continues to cause significant global mortality in human populations. Given its sequence similarity to SARS-CoV, as well as related coronaviruses circulating in bats, SARS-CoV-2 is thought to have originated in Chiroptera species in China. However, whether the virus spread directly to humans or through an intermediate host is currently unclear, as is the potential for this virus to infect companion animals, livestock, and wildlife that could act as viral reservoirs. Using a combination of surrogate entry assays and live virus, we demonstrate that, in addition to human angiotensin-converting enzyme 2 (ACE2), the Spike glycoprotein of SARS-CoV-2 has a broad host tropism for mammalian ACE2 receptors, despite divergence in the amino acids at the Spike receptor binding site on these proteins. Of the 22 different hosts we investigated, ACE2 proteins from dog, cat, and cattle were the most permissive to SARS-CoV-2, while bat and bird ACE2 proteins were the least efficiently used receptors. The absence of a significant tropism for any of the 3 genetically distinct bat ACE2 proteins we examined indicates that SARS-CoV-2 receptor usage likely shifted during zoonotic transmission from bats into people, possibly in an intermediate reservoir. Comparison of SARS-CoV-2 receptor usage to the related coronaviruses SARS-CoV and RaTG13 identified distinct tropisms, with the 2 human viruses being more closely aligned. Finally, using bioinformatics, structural data, and targeted mutagenesis, we identified amino acid residues within the Spike-ACE2 interface, which may have played a pivotal role in the emergence of SARS-CoV-2 in humans. The apparently broad tropism of SARS-CoV-2 at the point of viral entry confirms the potential risk of infection to a wide range of companion animals, livestock, and wildlife.

Viral Tropism Virus Attachment Amino Acid Substitution Angiotensin-Converting Enzyme 2 Animals Binding Sites Cats Cattle Dogs Guinea Pigs HEK293 Cells Host-Pathogen Interactions Humans Rabbits Rats SARS-CoV-2 Spike Glycoprotein, Coronavirus Viral Zoonoses

Structured evidence records

Evidence records

10 total

Host Range Experiment 5 records

Host Range Experiment Extraction confidence 0.95

Key finding

SARS-CoV-2 Spike exhibited broad host tropism in surrogate entry and live virus assays, showing efficient usage of dog, cat, and cattle ACE2 and poor usage of bat and bird ACE2.

Virus

Host

Location

Supporting text

Using a combination of surrogate entry assays and live virus, we demonstrate that, in addition to human angiotensin-converting enzyme 2 (ACE2), the Spike glycoprotein of SARS-CoV-2 has a broad host tropism for mammalian ACE2 receptors. Of the 22 different hosts we investigated, ACE2 proteins from dog, cat, and cattle were the most permissive to SARS-CoV-2, while bat and bird ACE2 proteins were the least efficiently used receptors.

Method: surrogate entry assay; live virus assay
Experimental system: in vitro cell culture

Host Range Experiment Extraction confidence 0.95

Key finding

SARS-CoV-2 Spike efficiently utilized cat ACE2 for cell entry in surrogate entry and live virus assays.

Virus

Host

Location

Supporting text

Method: surrogate entry assay; live virus assay
Experimental system: in vitro cell culture

Host Range Experiment Extraction confidence 0.95

Key finding

SARS-CoV-2 Spike efficiently utilized cattle ACE2 for viral entry in experimental assays.

Virus

Host

Location

Supporting text

Method: surrogate entry assay; live virus assay
Experimental system: in vitro cell culture

Host Range Experiment Extraction confidence 0.95

Key finding

SARS-CoV-2 Spike showed inefficient use of bat ACE2 receptors in experimental assays.

Virus

Host

Location

Supporting text

Of the 22 different hosts we investigated, ACE2 proteins from dog, cat, and cattle were the most permissive to SARS-CoV-2, while bat and bird ACE2 proteins were the least efficiently used receptors.

Method: surrogate entry assay; live virus assay
Experimental system: in vitro cell culture

Host Range Experiment Extraction confidence 0.95

Key finding

SARS-CoV-2 Spike showed inefficient use of bird ACE2 receptors in comparative host-range assays.

Virus

Host

Location

Supporting text

Of the 22 different hosts we investigated, ACE2 proteins from dog, cat, and cattle were the most permissive to SARS-CoV-2, while bat and bird ACE2 proteins were the least efficiently used receptors.

Method: surrogate entry assay; live virus assay
Experimental system: in vitro cell culture

Receptor Usage 4 records

Receptor Usage Extraction confidence 1.00

Key finding

SARS-CoV-2 Spike uses ACE2 receptors from multiple mammalian species, showing highest compatibility with dog, cat, and cattle ACE2 and poor utilization of bat and bird ACE2.

Virus

Host

Location

Supporting text

Using surrogate entry assays and live virus, we demonstrate that, in addition to human angiotensin-converting enzyme 2 (ACE2), the Spike glycoprotein of SARS-CoV-2 has a broad host tropism for mammalian ACE2 receptors. Of the 22 different hosts investigated, ACE2 proteins from dog, cat, and cattle were the most permissive to SARS-CoV-2, while bat and bird ACE2 proteins were the least efficiently used receptors.

Method: surrogate entry assay; live virus assay
Receptors: ACE2

Receptor Usage Extraction confidence 1.00

Key finding

SARS-CoV-2 uses cat ACE2 efficiently for entry.

Virus

Host

Location

Supporting text

ACE2 proteins from dog, cat, and cattle were the most permissive to SARS-CoV-2, while bat and bird ACE2 proteins were the least efficiently used receptors.

Method: surrogate entry assay; live virus assay
Receptors: ACE2

Receptor Usage Extraction confidence 1.00

Key finding

SARS-CoV-2 uses cattle ACE2 efficiently for entry.

Virus

Host

Location

Supporting text

ACE2 proteins from dog, cat, and cattle were the most permissive to SARS-CoV-2, while bat and bird ACE2 proteins were the least efficiently used receptors.

Method: surrogate entry assay; live virus assay
Receptors: ACE2

Receptor Usage Extraction confidence 1.00

Key finding

SARS-CoV-2 Spike shows poor compatibility with bat ACE2 receptors.

Virus

Host

Location

Supporting text

ACE2 proteins from dog, cat, and cattle were the most permissive to SARS-CoV-2, while bat and bird ACE2 proteins were the least efficiently used receptors.

Method: surrogate entry assay; live virus assay
Receptors: ACE2

Molecular Adaptation 1 records

Molecular Adaptation Extraction confidence 0.90

Key finding

SARS-CoV-2 Spike protein has adapted to efficiently use diverse mammalian ACE2 receptors, with specific amino acid residues in the Spike–ACE2 binding interface contributing to host range and human emergence.

Virus

Host

Location

Supporting text

Using surrogate entry assays and live virus, we demonstrate that the Spike glycoprotein of SARS-CoV-2 has a broad host tropism for mammalian ACE2 receptors, despite divergence in amino acids at the Spike receptor binding site. Targeted mutagenesis identified residues within the Spike–ACE2 interface that may have played a pivotal role in the emergence of SARS-CoV-2 in humans.

Genes or proteins: Spike; ACE2
Receptors: ACE2
Mechanism types: receptor_binding; tropism; host_range_adaptation

Citation context

References

53 references

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Evidence overview

Evidence 10

Types 3

Virus 1

Host 5

Evidence types

Host Range Experiment 5 Receptor Usage 4 Molecular Adaptation 1

Linked entities

Viruses

Hosts

Locations

Publication metadata

Journal: PLoS biology
Volume / Issue / Pages: 18 / 12 / e3001016
ISSN: 1545-7885
Journal country: United States
DOI: 10.1371/journal.pbio.3001016