SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals

Abstract

SARS-CoV-2 has a zoonotic origin and was transmitted to humans via an undetermined intermediate host, leading to infections in humans and other mammals. To enter host cells, the viral spike protein (S-protein) binds to its receptor, ACE2, and is then processed by TMPRSS2. Whilst receptor binding contributes to the viral host range, S-protein:ACE2 complexes from other animals have not been investigated widely. To predict infection risks, we modelled S-protein:ACE2 complexes from 215 vertebrate species, calculated changes in the energy of the complex caused by mutations in each species, relative to human ACE2, and correlated these changes with COVID-19 infection data. We also analysed structural interactions to better understand the key residues contributing to affinity. We predict that mutations are more detrimental in ACE2 than TMPRSS2. Finally, we demonstrate phylogenetically that human SARS-CoV-2 strains have been isolated in animals. Our results suggest that SARS-CoV-2 can infect a broad range of mammals, but few fish, birds or reptiles. Susceptible animals could serve as reservoirs of the virus, necessitating careful ongoing animal management and surveillance.

Figure 1

Overview of SARS-CoV-2 S-protein:human ACE2 complex and interface. (a) SARS-CoV-2 S-protein RBD (light blue, purple) showing the receptor binding motif (purple) at the interface with ACE2 (tan). (b) residues in the SARS-CoV-2 S-protein:human ACE2 complex interface. Key RBD interface residues are shown (purple) with a subset of ACE2 contact residues that are not conserved in vertebrates for DC (red) and DCEX residues (blue) (PDB ID 6M0J).

Figure 2

Phylogenetic tree of species that humans come into close contact with in domestic, agricultural or zoological settings. Leaves are annotated by the change in energy of the complex (ΔΔG), as measured by protocol 2 mCSM-PPI2. Animals are categorised according to risk of infection by SARS-CoV-2, with ΔΔG ≤ 3.7 being at risk (red), and ΔΔG > 3.7 not at risk (blue). These thresholds were chosen as they agree well with the available experimental data (Fig. 3). For each animal, the sequence identity to the human ACE2 sequence, the number of mutated residues compared to the human ACE2 sequence, and the total chemical shift (measured by Grantham score—see Supplementary Methods 5) across the DCEX residues are also shown. This tree contains a subset of animals from Supplementary Fig. 7. Animal photos courtesy of ENSEMBL and associated sources (https://www.ensembl.org/info/about/image_credits.html).

Figure 3

Changes in energy of S-protein:ACE2 complex for animals that can be infected by SARS-CoV-2. Boxplots of ΔΔG values calculated by protocol 2 mCSM-PPI2 are shown. Infected: 32 animals that have in vivo or in vitro or real world evidence of infection. Not infected: 9 animals that have been experimentally tested but show no infection. All: 212 animals that were included in this study. The one-sided P value is reported from a Mann–Whitney test of the hypothesis that ΔΔG values from infected animals is lower than for not infected animals, against the null hypothesis that there is no difference between the two distributions.

Figure 4

Comparison of Grantham score sums for ASCSEX residues in ACE2 and TMPRSS2.

Figure 5

Phylogeny of SARS-like viruses. (a) Genome-wide maximum likelihood phylogenetic tree of SARS-like betacoronavirus strains sampled from diverse hosts (coloured tip symbols provide host and species; Supplementary Table 4). Genomes EPI_ISL_402131 and EPI_ISL_412977 are samples from RaTG13 and RmYN02 isolated from horseshoe bat hosts (Rhinolophus affinis and R. malayanus respectively). (b) Pairwise amino acid differences (color scale) at the S-protein RBD between human and animal associated strains of SARS-CoV-2, relative to closely related SARS-like viruses in bat and pangolin hosts.

Figure 6

Mammals that humans come into contact with that are at risk of infection by SARS-CoV-2. Twenty-six mammals are categorised into domestic, agricultural or zoological settings. Numbers represent the change in binding energy (ΔΔG) of the S-protein:ACE2.