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Evaluating angiotensin-converting enzyme 2-mediated SARS-CoV-2 entry across species.

Hong-Liang Zhang1 Yu-Ming Li2 Jing Sun2 Yu-Yuan Zhang1 Tong-Yun Wang1 Ming-Xia Sun1 Meng-Hang Wang1 Yue-Lin Yang1 Xiao-Liang Hu3 Yan-Dong Tang4 Jincun Zhao5 Xuehui Cai6
Affiliations 6 institutions
  1. State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, China.
  2. State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  3. School of Life Sciences and Food Engineering, Yibin University, Yibin Key Laboratory of Zoological Diversity and Ecological Conservation, Yibin, China.
  4. State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, China. Electronic address: [email protected].
  5. State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. Electronic address: [email protected].
  6. State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, China. Electronic address: [email protected].
PMID 33610551 2021 J Biol Chem eng ppublish
PubMed DOI Browse context

Article

Publication summary

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic represents a global threat, and the interaction between the virus and angiotensin-converting enzyme 2 (ACE2), the primary entry receptor for SARS-CoV-2, is a key determinant of the range of hosts that can be infected by the virus. However, the mechanisms underpinning ACE2-mediated viral entry across species remains unclear. Using infection assay, we evaluated SARS-CoV-2 entry mediated by ACE2 of 11 different animal species. We discovered that ACE2 of Rhinolophus sinicus (Chinese rufous horseshoe bat), Felis catus (domestic cat), Canis lupus familiaris (dog), Sus scrofa (wild pig), Capra hircus (goat), and Manis javanica (Malayan pangolin) facilitated SARS-CoV-2 entry into nonsusceptible cells. Moreover, ACE2 of the pangolin also mediated SARS-CoV-2 entry, adding credence to the hypothesis that SARS-CoV-2 may have originated from pangolins. However, the ACE2 proteins of Rhinolophus ferrumequinum (greater horseshoe bat), Gallus gallus (red junglefowl), Notechis scutatus (mainland tiger snake), or Mus musculus (house mouse) did not facilitate SARS-CoV-2 entry. In addition, a natural isoform of the ACE2 protein of Macaca mulatta (rhesus monkey) with the Y217N mutation was resistant to SARS-CoV-2 infection, highlighting the possible impact of this ACE2 mutation on SARS-CoV-2 studies in rhesus monkeys. We further demonstrated that the Y217 residue of ACE2 is a critical determinant for the ability of ACE2 to mediate SARS-CoV-2 entry. Overall, these results clarify that SARS-CoV-2 can use the ACE2 receptors of multiple animal species and show that tracking the natural reservoirs and intermediate hosts of SARS-CoV-2 is complex.

ACE2 cross-species pangolin SARS-CoV-2 susceptibility Pandemics Angiotensin-Converting Enzyme 2 Animals Cats Chickens Chiroptera COVID-19 Dogs Elapidae Eutheria Gene Expression Goats HEK293 Cells

Structured evidence records

Evidence records

7 total
Receptor Usage 3 records
Receptor Usage Extraction confidence 1.00
Key finding

ACE2 from Rhinolophus sinicus, Felis catus, Canis lupus familiaris, Sus scrofa, Capra hircus, and Manis javanica mediated SARS-CoV-2 entry, indicating receptor compatibility across these species.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

We discovered that ACE2 of Rhinolophus sinicus (Chinese rufous horseshoe bat), Felis catus (domestic cat), Canis lupus familiaris (dog), Sus scrofa (wild pig), Capra hircus (goat), and Manis javanica (Malayan pangolin) facilitated SARS-CoV-2 entry into nonsusceptible cells.

Method
infection assay
Receptors
ACE2
Receptor Usage Extraction confidence 1.00
Key finding

ACE2 from Rhinolophus ferrumequinum, Gallus gallus, Notechis scutatus, and Mus musculus did not mediate SARS-CoV-2 entry, showing receptor incompatibility.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

The ACE2 proteins of Rhinolophus ferrumequinum (greater horseshoe bat), Gallus gallus (red junglefowl), Notechis scutatus (mainland tiger snake), or Mus musculus (house mouse) did not facilitate SARS-CoV-2 entry.

Method
infection assay
Receptors
ACE2
Receptor Usage Extraction confidence 1.00
Key finding

The Y217N mutation in Macaca mulatta ACE2 confers resistance to SARS-CoV-2 entry, indicating that residue Y217 is critical for receptor-mediated infection.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

A natural isoform of the ACE2 protein of Macaca mulatta (rhesus monkey) with the Y217N mutation was resistant to SARS-CoV-2 infection, highlighting the possible impact of this ACE2 mutation on SARS-CoV-2 studies in rhesus monkeys.

Method
infection assay
Receptors
ACE2
Host Range Experiment 2 records
Host Range Experiment Extraction confidence 0.95
Key finding

Cell-based infection assays showed that SARS-CoV-2 can enter cells expressing ACE2 from bat, cat, dog, pig, goat, and pangolin, but not from greater horseshoe bat, chicken, tiger snake, or mouse.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

Using infection assay, we evaluated SARS-CoV-2 entry mediated by ACE2 of 11 different animal species. We discovered that ACE2 of Rhinolophus sinicus (Chinese rufous horseshoe bat), Felis catus (domestic cat), Canis lupus familiaris (dog), Sus scrofa (wild pig), Capra hircus (goat), and Manis javanica (Malayan pangolin) facilitated SARS-CoV-2 entry into nonsusceptible cells, while ACE2 of Rhinolophus ferrumequinum, Gallus gallus, Notechis scutatus, or Mus musculus did not.

Method
infection assay; cell-entry assay
Experimental system
in vitro cell culture
Host Range Experiment Extraction confidence 0.95
Key finding

An ACE2 Y217N variant in rhesus monkey was resistant to SARS-CoV-2 infection in cell assays, indicating reduced host susceptibility.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

A natural isoform of the ACE2 protein of Macaca mulatta (rhesus monkey) with the Y217N mutation was resistant to SARS-CoV-2 infection, highlighting the possible impact of this ACE2 mutation on SARS-CoV-2 studies in rhesus monkeys.

Method
infection assay; cell-entry assay
Experimental system
in vitro cell culture
Molecular Adaptation 2 records
Molecular Adaptation Extraction confidence 0.90
Key finding

The Y217 residue in rhesus monkey ACE2 determines susceptibility to SARS-CoV-2 entry, with the Y217N mutation conferring resistance to infection.

Virus
SARS-CoV-2
Host
Not specified
Location
Not specified
Supporting text

A natural isoform of the ACE2 protein of Macaca mulatta (rhesus monkey) with the Y217N mutation was resistant to SARS-CoV-2 infection, highlighting the possible impact of this ACE2 mutation on SARS-CoV-2 studies in rhesus monkeys. We further demonstrated that the Y217 residue of ACE2 is a critical determinant for the ability of ACE2 to mediate SARS-CoV-2 entry.

Genes or proteins
ACE2; Spike Glycoprotein
Receptors
ACE2
Mutations
Y217N
Mechanism types
receptor_binding; cell_entry; pathogenicity
Molecular Adaptation Extraction confidence 0.90
Key finding

ACE2 receptors from several mammalian species mediated SARS-CoV-2 entry, demonstrating cross-species receptor binding adaptation.

Virus
SARS-CoV-2
Host
Not specified
Location
Not specified
Supporting text

ACE2 of Rhinolophus sinicus, Felis catus, Canis lupus familiaris, Sus scrofa, Capra hircus, and Manis javanica facilitated SARS-CoV-2 entry into nonsusceptible cells.

Genes or proteins
ACE2; Spike Glycoprotein
Receptors
ACE2
Mechanism types
receptor_binding; cell_entry; host_range