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. 2023 Nov 27;20(1):276.
doi: 10.1186/s12985-023-02222-9.

Susceptibility of bovine to SARS-CoV-2 variants of concern: insights from ACE2, AXL, and NRP1 receptors

Ying Ma  1 , Mengyue Lei  1 , Hongli Chen  1   2 , Pu Huang  1 , Jing Sun  3 , Qiangming Sun  4 , Yunzhang Hu  5 , Jiandong Shi  6   7
Affiliations

Susceptibility of bovine to SARS-CoV-2 variants of concern: insights from ACE2, AXL, and NRP1 receptors

Ying Ma et al. Virol J. .

Abstract

The possibilities of cross-species transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between humans and important livestock species are not yet known. Herein, we used the structural and genetic alignment and surface potential analysis of the amino acid (aa) in angiotensin-converting enzyme 2 (ACE2), tyrosine kinase receptor UFO (AXL), and neuropilin 1 (NRP1) in different species with substantial public health importance. The residues interfacing with the N-terminal domain (NTD) or receptor-binding domain (RBD) of S were aligned to screen the critical aa sites that determined the susceptibility of the SARS-CoV-2 to the host. We found that AXL and NRP1 proteins might be used as the receptors of SARS-CoV-2 in bovines. However, ACE2 protein may not be considered to be involved in the cross-species transmission of SARS-CoV-2 VOCs in cattle because the key residues of the ACE2-S-binding interface were different from those in known susceptible species. This study indicated that emerging SARS-CoV-2 variants potentially expand species tropism to bovines through AXL and NRP1 proteins.

Keywords: ACE2; AXL; Cross-species transmission; NRP1; Receptor; SARS-CoV-2 variants.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Alignment and electrostatic surface potential analysis of key amino acids residues of ACE2. A Sequence alignment analysis of the interface binding between ACE2 and S of SARS-CoV-2 from minks (GenBank accession no. XP_044091953.1), ferrets (GenBank accession no. NP_001297119.1), rhesus monkeys (GenBank accession no. NP_001129168.1), humans (GenBank accession no. NP_001358344.1), mice (GenBank accession no. NP_001123985.1), hamsters (GenBank accession no. XP_003503283.1) and bovines (GenBank accession no. NP_001019673.2). The ACE2 residues at positions 342, 368, 386, 502, and 507 are marked with blue triangles. B Electrostatic surface potential diagram of ACE2s in different species. The structural superposition of the ACE2 region 341–480 from cattle (green), minks (brown), ferrets (cyan), mice (gray), hamsters (pink), humans (khaki), and rhesus monkeys (blue) is in the center. The homology models of human ACE2 (PDBID 6m18) were used to compare the ACE2 structures of cattle, minks, ferrets, mice, hamsters, and rhesus monkeys. The tertiary structure was predicted using SWISS-MODEL. The yellow sticks highlight the five key differential residues of ACE2 binding with S of SARS-CoV-2. The details are circled using a dashed line in each electrostatic surface potential map. The electrostatic potential color range is –/ + 5
Fig. 2
Fig. 2
Alignment and electrostatic surface potential analysis of key amino acids residues of AXL. A Sequence alignment analysis of the interface binding between ACE2 and S of SARS-CoV-2 from ferrets (GenBank accession no. XP_004776133.1), minks (GenBank accession no. XP_044113292.1), bovines (GenBank accession no. XP_024834863.1), humans (GenBank accession no. NP_068713.2), rhesus monkeys (GenBank accession no. XP_028695606.1), hamsters (GenBank accession no. XP_035292416.1), and mice (GenBank accession no. XP_006540052.1). The ALX residues at positions 61, 68, 85, 113, 115, and 116 are marked with blue triangles. B Electrostatic surface potential diagram of AXLs in different species. The structural superposition of the AXL region 29–127 from cattle (green), minks (brown), ferrets (cyan), mice (gray), hamsters (pink), humans (khaki), and rhesus monkeys (blue) is in the center. The homology models of human AXL (PDBID 4yfg) were used to compare the AXL structures of cattle, minks, ferrets, mice, hamsters, and rhesus monkeys. The tertiary structure was predicted using SWISS-MODEL. The yellow sticks highlight the six key differential resides of AXL binding with S of SARS-CoV-2. The details are circled using a dashed line in each electrostatic surface potential map. The electrostatic potential color range is –/ + 5
Fig. 3
Fig. 3
Alignment and electrostatic surface potential analysis of key amino acids residues of NRP1. A Sequence alignment analysis of the interface binding between NRP1 and S of SARS-CoV-2 from humans (GenBank accession no. XP_006717584.1), rhesus monkeys (GenBank accession no. NP_001252745.1), ferrets (GenBank accession no. XP_004774343.2), minks (GenBank accession no. XP_044082878.1), bovines (GenBank accession no. NP_001192589.1), hamsters (GenBank accession no. XP_007647231.1), and mice (GenBank accession no. XP_0065430829.1). The NRP1 residues at positions 35 and 90 are marked with blue triangles. B Electrostatic surface potential diagram of ACE2s in different species. The structural superposition of the NRP1 region 28–140 from cattle (green), minks (brown), ferrets (cyan), mice (gray), hamsters (pink), humans (khaki), and rhesus monkeys (blue) is in the center. The homology models of human NRP1 (PDBID 7m0r) were used to compare the NRP1 structures of cattle, minks, ferrets, mice, hamsters, and rhesus monkeys. The tertiary structure was predicted using SWISS-MODEL. The yellow sticks highlight the two key differential resides of NRP1 binding with S of SARS-CoV-2. The details are circled using a dashed line in each electrostatic surface potential map. The electrostatic potential color range is –/ + 5
Fig. 4
Fig. 4
Sequence alignment of S protein from three SARS-CoV-2 strains, including Wuhan-Hu-1 (GenBank accession no. YP_009724390), delta variant (GenBank accession no. QYM88683), and omicron variant (GenBank accession no. UFS23237). A The important residues in RBD of S interacting with ACE2 and NRP1 are marked with green stars. B The important residues in NTD of S interacting with AXL are marked with green stars
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