Origin and evolution of pathogenic coronaviruses

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are two highly transmissible and pathogenic viruses that emerged in humans at the beginning of the 21st century. Both viruses likely originated in bats, and genetically diverse coronaviruses that are related to SARS-CoV and MERS-CoV were discovered in bats worldwide. In this Review, we summarize the current knowledge on the origin and evolution of these two pathogenic coronaviruses and discuss their receptor usage; we also highlight the diversity and potential of spillover of bat-borne coronaviruses, as evidenced by the recent spillover of swine acute diarrhoea syndrome coronavirus (SADS-CoV) to pigs.

Fig. 1. The genomes, genes and proteins of different coronaviruses.

Coronaviruses form enveloped and spherical particles of 100–160 nm in diameter. They contain a positive-sense, single-stranded RNA (ssRNA) genome of 27–32 kb in size. The 5'-terminal two-thirds of the genome encodes a polyprotein, pp1ab, which is further cleaved into 16 non-structural proteins that are involved in genome transcription and replication. The 3' terminus encodes structural proteins, including envelope glycoproteins spike (S), envelope (E), membrane (M) and nucleocapsid (N). In addition to the genes encoding structural proteins, there are accessory genes that are species-specific and dispensable for virus replication. Here, we compare prototypical and representative strains of four coronavirus genera: feline infectious peritonitis virus (FIPV), Rhinolophus bat coronavirus HKU2, severe acute respiratory syndrome coronavirus (SARS-CoV) strains GD02 and SZ3 from humans infected during the early phase of the SARS epidemic and from civets, respectively, SARS-CoV strain hTor02 from humans infected during the middle and late phases of the SARS epidemic, bat SARS-related coronavirus (SARSr-CoV) strain WIV1, Middle East respiratory syndrome coronavirus (MERS-CoV), mouse hepatitis virus (MHV), infectious bronchitis virus (IBV) and bulbul coronavirus HKU11.

Fig. 2. Animal origins of human coronaviruses.

Severe acute respiratory syndrome coronavirus (SARS-CoV) is a new coronavirus that emerged through recombination of bat SARS-related coronaviruses (SARSr-CoVs). The recombined virus infected civets and humans and adapted to these hosts before causing the SARS epidemic^,. Middle East respiratory syndrome coronavirus (MERS-CoV) likely spilled over from bats to dromedary camels at least 30 years ago and since then has been prevalent in dromedary camels. HCoV-229E and HCoV-NL63 usually cause mild infections in immunocompetent humans. Progenitors of these viruses have recently been found in African bats^,, and the camelids are likely intermediate hosts of HCoV-229E^,. HCoV-OC43 and HKU1, both of which are also mostly harmless in humans, likely originated in rodents. Recently, swine acute diarrhoea syndrome (SADS) emerged in piglets. This disease is caused by a novel strain of Rhinolophus bat coronavirus HKU2, named SADS coronavirus (SADS-CoV); there is no evidence of infection in humans. Solid arrows indicate confirmed data. Broken arrows indicate potential interspecies transmission. Black arrows indicate infection in the intermediate animals, yellow arrows indicate a mild infection in humans, and red arrows indicate a severe infection in humans or animals.

Fig. 3. Phylogenetic relationships in the Coronavirinae subfamily.

The highly human-pathogenic coronaviruses belong to the subfamily Coronavirinae from the family Coronaviridae. The viruses in this subfamily group into four genera (prototype or representative strains shown): Alphacoronavirus (purple), Betacoronavirus (pink), Gammacoronavirus (green) and Deltacoronavirus (blue). Classic subgroup clusters are labelled 1a and 1b for the alphacoronaviruses and 2a–2d for the betacoronaviruses. The tree is based on published trees of Coronavirinae^, and reconstructed with sequences of the complete RNA-dependent RNA polymerase-coding region of the representative coronaviruses (maximum likelihood method under the GTR + I + Γ model of nucleotide substitution as implemented in PhyML, version 3.1 (ref.)). Only nodes with bootstrap support above 70% are shown. IBV, infectious bronchitis virus; MERS-CoV, Middle East respiratory syndrome coronavirus; MHV, mouse hepatitis virus; PEDV, porcine enteric diarrhoea virus; SARS-CoV, severe acute respiratory syndrome coronavirus; SARSr-CoV, SARS-related coronavirus.

Fig. 4. Phylogenetic analysis of SARSr-CoVs and MERSr-CoVs.

a | The figure shows a simplified phylogenetic tree of severe acute respiratory syndrome-related coronaviruses (SARSr-CoVs) from bats. SARSr-CoVs cluster into three lineages, L1–L3, and human severe acute respiratory syndrome coronaviruses (SARS-CoVs) embed in L1. Two individual SARSr-CoVs do not cluster into these lineages: YN, a virus isolated from Yunnan province, China, and BG, a virus from Bulgaria, Europe. The tree is based on published trees^, and reconstructed using sequences of the complete RNA-dependent RNA polymerase-coding region (maximum likelihood method under the GTR + I + Γ model of nucleotide substitution as implemented in PhyML, version 3.1 (ref.)).The strain Zhejiang2013 (GenBank No. KF636752) was used as a root. b | By contrast, Middle East respiratory syndrome-related coronaviruses (MERSr-CoVs) form two major viral lineages, L1 and L2. L1 is found in humans and camels, and L2 is found only in camels. Two small clusters, B1 (bat 1) and B2, and one single virus, SA, from South Africa, were found in bats. The phylogenetic tree of MERSr-CoVs is based on a published trees^, and reconstructed using full-genome alignment of all coding regions using the same method as above. HKU4-1 (EF065505) and HKU5-1 (EF065509), two 2c betacoronaviruses, served as the root of the tree. Detailed phylogenetic trees and grouping information can be found in Supplementary Fig. S1. MERS-CoV, Middle East respiratory syndrome coronavirus.

Fig. 5. Variable regions in different SARS-CoV and bat SARSr-CoV isolates.

Variability and thus species adaptation majorly affect three severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-related coronavirus (SARSr-CoV) proteins: the spike protein (S) (both the S1 amino-terminal domain (S1-NTD) and the S1 receptor-binding domain (S1-RBD) show variability), ORF3 (3a and 3b) and ORF8 (8a and b). SARS-CoV GD02 and hTor02 represent strains that were isolated from patients during the early, and middle or late phase of the SARS epidemic in 2002–2003, respectively; SARS-CoV CZ3 is a representative of strains isolated from civets in 2003 and 2004 (refs^,). All bat SARSr-CoVs, except HKU3 and Rp3, were discovered in Yunnan province during 2011–2015. On the basis of deletions in the RBD, bat SARSr-CoVs can be divided into two clades. Those without a deletion and thus an identical size in S1 to SARS-CoV can be further divided into four genotypes: genotype 1, represented by WIV16, is highly similar to SARS-CoV in both the NTD and the RBD; genotype 2, represented by WIV1, differs in NTD from SARS-CoV; genotype 3, represented by Rs4231, differs in RBD from SARS-CoV; and genotype 4, represented by SHC014 and Rs4084, differs in both NTD and RBD from SARS-CoV. The differences in S influence species-specific receptor binding, whereas differences in the accessory proteins, including potentially the newly discovered ORFX (X), mainly affect immune responses and viral immune evasion. Adapted from ref., CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).

Fig. 6. Receptor recognition by SARS-CoV and MERS-CoV.

a | Severe acute respiratory syndrome coronavirus (SARS-CoV) uses its receptor-binding domain (RBD) (as shown in the structure of strain hTor02, containing core structure (cyan) and receptor-binding motif (RBM; magenta)) to bind human angiotensin-converting enzyme 2 (ACE2; green; Protein Data Bank ID: 2AJF). ACE2 is a peptidase with zinc (blue) in its active centre. b | Several residues in the host and viral receptor, as well as two salt bridges that stabilize the structure (dotted lines) and form two binding hot spots, are crucial for binding of the severe acute respiratory syndrome (SARS) epidemic strain hTor02. Hydrophobic residues surrounding the two salt bridges are present in the structure but are not shown in the figure. c | By contrast, the SARS-related coronavirus (SARSr-CoV) strain bWIV1, which was isolated from bats and can infect both civet and human cells, differs in residues 442, 472 and 487. The mutation from threonine to asparagine in residue 487 introduces a polar side chain and is predicted to interfere with binding at hot spot 353. The model shown here was built on the basis of the structure of hTor02 RBD complexed with human ACE2 (Protein Data Bank ID: 2AJF), in which residues 442, 472 and 487 were mutated from those in strain hTor02 to those in strain bWIV1. d | The bat SARSr-CoV strain bRsSHC014 can also infect human and civet cells; it carries an alanine in position 487, and the short side chain of this residue does not support the structure of hot spot 353. The model was built on the basis of the structure of cOptimize RBD complexed with human ACE2 (Protein Data Bank ID: 3SCJ), in which residues 442, 480 and 487 were mutated from those in strain cOptimize to those in strain bWIV1. e | The Middle East respiratory syndrome coronavirus (MERS-CoV) RBD (core structure in cyan and RBM in magenta) binds human dipeptidyl peptidase 4 (DPP4; green; Protein Data Bank ID: 4KR0). Structure figures were made using PyMOL. Modelled mutations in panels c and d were performed using Coot. Panels a–d are adapted from ref.: this research was originally published in The Journal of Biological Chemistry. Wu, K. L., Peng, G. Q., Wilken, M., Geraghty, R. J. & Li, F. Mechanisms of host receptor adaptation by severe acute respiratory syndrome coronavirus. J. Biol. Chem. 2012; 287:8904–8911. © American Society for Biochemistry and Molecular Biology.