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. 2023 Aug 29;20(1):196.
doi: 10.1186/s12985-023-02123-x.

Emerging SARS-CoV-2 variants of concern potentially expand host range to chickens: insights from AXL, NRP1 and ACE2 receptors

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

Emerging SARS-CoV-2 variants of concern potentially expand host range to chickens: insights from AXL, NRP1 and ACE2 receptors

Mengyue Lei et al. Virol J. .

Abstract

Background: The possibilities of cross-species transmission of SARS-CoV-2 variants of concern (VOCs) between humans and poultry species are unknown. The analysis of the structure of receptor was used to investigate the potential of emerging SARS-CoV-2 VOCs to expand species tropism to chickens based on the interaction between Spike (S) protein and tyrosine kinase receptor UFO (AXL), angiotensin-converting enzyme 2 (ACE2), and neuropilin 1 (NRP1) with substantial public health importance.

Methods: The structural and genetic alignment and surface potential analysis of the amino acid (aa) in ACE2, AXL, and NRP1 in human, hamster, mouse, mink, ferret, rhesus monkey and chickens were performed by Swiss-Model and pymol software. The critical aa sites that determined the susceptibility of the SARS-CoV-2 to the host were screened by aligning the residues interfacing with the N-terminal domain (NTD) or receptor-binding domain (RBD) of Spike protein.

Results: The binding modes of chickens AXL and ACE2 to S protein are similar to that of the ferret. The spatial structure and electrostatic surface potential of NRP1 showed that SARS-CoV-2 VOCs could not invade chickens through NRP1 easily.

Conclusion: These results suggested that emerging SARS-CoV-2 VOCs potentially expand the host range to chickens mainly through ACE2 and AXL receptors, while NRP1 receptor may rarely participate in the future epidemic of coronavirus disease 2019 in chickens.

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

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Conflict of interest statement

The authors declare no competing interests.

The authors declare that there is no conflict of interest.

Figures

Fig. 1
Fig. 1
Alignment and surface potential analysis of crucial amino acids in AXL proteins. (A) Comparative analysis of the residues of AXLs at the interface binding to the spike of SARS-CoV-2 from human (GenBank accession no. NP_068713.2), rhesus (GenBank accession no. XP_028695606.1), hamster (GenBank accession no. XP_035292416.1), mouse (GenBank accession no. XP_006540052.1), ferret (GenBank accession no. XP_004776133. 1), mink (GenBank accession no. XP_044113292.1), and chickens (GenBank accession no. NP_989958. 2). ALX residues at position 61, 68, 113, 115, and 116 are marked in blue triangles. (B) Surface diagram of interface zone of AXLs. The structural superposition of the AXL region 29–127 from human (yellow, PDB code 4yfg), rhesus (violet), hamster (purple), mouse (gray), ferret (cyan), mink (red), and chickens (green). The AXL structures of chickens, rhesus, hamster, mouse, ferret, and mink were constructed using the homology models of human AXL (PDB code 4yfg) as the templates by SWISS-MODEL (https://swissmodel.expasy.org/). The five key differential residues of AXL interacting with spike protein of SARS-CoV-2 are represented by yellow sticks in the structural superposition, the black dash line circled key residues in the potential surface diagram. The electrostatic potential color range is -/+5
Fig. 2
Fig. 2
Alignment and surface potential analysis of crucial amino acids in NRP1 proteins. (A) Comparative analysis of the residues of NRP1s at the interface binding to the spike protein of SARS-CoV-2 from human (GenBank accession no. XP_006717584.1), rhesus (GenBank accession no. NP_001252745.1), hamster (GenBank accession no. XP_040590606), mouse (GenBank accession no. NP_033491), ferret (GenBank accession no. XP_004774343.2), mink (GenBank accession no. XP_044082878.1), and Gallus (GenBank accession no. NP_990113.1). The NRP1 residues at positions 35, 46, and 90 are marked in blue triangles. (B) Surface potential diagram of interface zone of NRP1s. The structural superposition of the NRP1 region 26–141 from human (yellow, PDB code 7m0r), rhesus (violet), hamster (purple), mouse (gray), ferret (cyan), mink (red), and chickens (green). The NRP1 structures of chickens, rhesus, hamster, ferret, and mink were modeled using the homology models of human NRP1 (PDB code 7m0r) as the template by SWISS-MODEL (https://swissmodel.expasy.org/). The three key differential residues of NRP1 interacting with the spike protein of SARS-CoV-2 are represented by yellow sticks in the structural superposition; the black dash line circled key residues in the potential surface diagram. The electrostatic potential color range is -/+5
Fig. 3
Fig. 3
Alignment and surface potential analysis of crucial amino acids in ACE2 proteins. (A) Comparative analysis of the residues of ACE2s at the interface binding to the spike protein of SARS-CoV-2 from human (GenBank accession no. NP_001358344.1), rhesus (GenBank accession no. NP_001129168.1), hamster (GenBank accession no. XP_003503283.1), mouse (GenBank accession no. NP_001123985.1), ferret (GenBank accession no. NP_001297119.1), mink (GenBank accession no. XP_044091953), and chickens (GenBank accession no. XP_040517014.1). The ACE2 residues at positions 368, 380, 386, 502, and 507 are marked in blue triangles. (B) Surface potential diagram of interface zone of ACE2s. The structural superposition of the ACE2 region 366–520 from human (yellow, PDB code 6m18), rhesus (violet), hamster (purple), mouse (gray, UniProt entry Q0093), ferret (cyan), mink (red), and chickens (green). The ACE2 structures of chickens, rhesus, hamster, ferret, and mink were modeled using the homology models of human ACE2 (PDB code 6m18) as the templates by SWISS-MODEL (https://swis-smodel.expasy.org/). The five key differential residues of ACE2 interacting with the spike protein of SARS-CoV-2 are represented by yellow sticks in the structural superposition, the black dash line indicates the key residues in the potential surface diagram. The electrostatic potential color range is -/+5
Fig. 4
Fig. 4
Sequence alignment of spike protein from three SARS-CoV-2 strains, including Wuhan-Hu-1 (GenBank accession no.YP_009724390.1), Delta variant (GenBank accession no. QYM88683.1), and Omicron variant (GenBank accession no. EPI_ISL_12943352). The critical residues in NTD of S interacting with AXL (A), CendR of S interacting with NRP1 (B), and RBD of S interacting with ACE2 (C) are marked with green stars or blue triangles
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