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Review
. 2010 Apr;84(7):3134-46.
doi: 10.1128/JVI.01394-09. Epub 2009 Nov 11.

Recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission

Rachel L Graham  1 , Ralph S Baric
Affiliations
Review

Recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission

Rachel L Graham et al. J Virol. 2010 Apr.

Abstract

Over the past 30 years, several cross-species transmission events, as well as changes in virus tropism, have mediated significant animal and human diseases. Most notable is severe acute respiratory syndrome (SARS), a lower respiratory tract disease of humans that was first reported in late 2002 in Guangdong Province, China. The disease, which quickly spread worldwide over a period of 4 months spanning late 2002 and early 2003, infected over 8,000 individuals and killed nearly 800 before it was successfully contained by aggressive public health intervention strategies. A coronavirus (SARS-CoV) was identified as the etiological agent of SARS, and initial assessments determined that the virus crossed to human hosts from zoonotic reservoirs, including bats, Himalayan palm civets (Paguma larvata), and raccoon dogs (Nyctereutes procyonoides), sold in exotic animal markets in Guangdong Province. In this review, we discuss the molecular mechanisms that govern coronavirus cross-species transmission both in vitro and in vivo, using the emergence of SARS-CoV as a model. We pay particular attention to how changes in the Spike attachment protein, both within and outside of the receptor binding domain, mediate the emergence of coronaviruses in new host populations.

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Figures

FIG. 1.
FIG. 1.
Schematic representation of SARS-CoV genome and civet and bat strain conservation. (Top) SARS-CoV genome is shown, with ORF1a/ORF1b proteolytic sites indicated by vertical bars and arrows. Nonstructural protein (nsp) numbers are indicated above. The color of the arrows corresponds to the proteinase responsible for cleavage: red, papain-like proteinase (PLP); blue, 3C-like proteinase (3CLpro). ORFs 2 to 9 are indicated by individual boxes. Coronavirus-conserved proteins are indicated as follows: ORF2, Spike (S); ORF 4, Envelope (E); ORF5, Membrane (M); ORF 9a, Nucleocapsid (N). Sizes are approximately to scale. (Middle and bottom) Degree of conservation, protein-by-protein, compared to SARS-CoV (strain Urbani) is indicated by color. A color scale, with conservation expressed in percentages, is shown at the bottom. All comparisons represent degrees of conservation of amino acids and nucleotides, which are approximately equal, with the exceptions of ORF3 and ORF8. In these cases, amino acid conservation is indicated by the color in the top of the box, and nucleotide conservation is indicated by the color in the bottom of the box.
FIG. 2.
FIG. 2.
Comparison of class I viral fusion proteins. Examples of class I viral fusion proteins, including influenza HA, retrovirus Envelope, and the coronavirus Spike, are shown schematically, with the N terminus to the left and the C terminus to the right. The viral membrane is indicated by two dashed, vertical blue lines. Protein domains shown are as follows: fusion peptide, red; heptad repeat 1 (HR1), teal; heptad repeat 2 (HR2), dark blue; and CoV Spike receptor binding domain (RBD), purple. Proteolytic cleavage sites are indicated by orange triangles, and the names of subsequent subunits are indicated at the appropriate side of each triangle. Sizes and locations of domains are approximately to scale. The locations of identified mutations associated with host range expansion are indicated by red asterisks for point mutations and blue tildes (∼) for large domain swaps either within the RBD (purple box) or in the context of the rest of the protein (purple dashed line). References for each study are indicated in the text.
FIG. 3.
FIG. 3.
Comparison of SARS-like CoV Spike RBD variations. Spike RBD residues that are not conserved in comparison to the human strain are indicated by amino acid residue number (the RBD corresponds to human amino acid residues 319 to 518). Residues that are considered part of the receptor binding motif (RBM), the cassette containing the 14 residues that interact with human ACE2 (hACE2), are highlighted in red. RBM residues that have been identified as direct hACE2-interacting residues are numbered in black. Residues that vary from those of the human strain sequence are highlighted in blue. Residues that are absent in comparison to those of the human sequence are highlighted in yellow. The strains shown are as follows: BSCoV RP3, bat SARS-like CoV strain RP3; A031, a raccoon dog strain; HC/SZ/61/03 and SZ16, civet strains; GD03, a postepidemic human strain that clusters phylogenetically with civet strains (possible reemergent strain); GZ02, early-phase human strain; CUHK-W1, middle-phase human strain; and SARS-CoV, human late-phase epidemic Urbani strain.
FIG. 4.
FIG. 4.
Comparison of ACE2 residues that directly interact with Spike RBD. Species comparisons of ACE2 molecules for human, African green monkey (Chlorocebus aethiops), Himalayan palm civet (Paguma larvata), mouse (Mus musculus), and Chinese horseshoe bat (Rhinolophus sinicus) are shown. ACE2 residue numbers are indicated above the graph. Residues that differ from those of the human sequence are highlighted in blue. Residues that differ from but are homologous to human sequences are indicated in pink. Percent identity/homology to the human sequence is indicated to the right (BLOSUM62 alignment). SARS-CoV Spike RBD residues shown to interact with human ACE2 residues (72) are indicated at the bottom of each column. ACE2 residues shown to interact with Spike residues 479 and 487, which have demonstrated high relevance in host range studies (75), are indicated in yellow.
FIG. 5.
FIG. 5.
Paradigms for cross-species transmission of SARS-like CoVs. Host species are represented by black boxes. Viral genomes are represented by blue bars, and species-specific RBDs are indicated by colored boxes: red, bat specific; purple, civet specific; green, human (epidemic) specific. (A) The civet intermediate paradigm. The bat reservoir progenitor virus was transmitted to civets, and a civet-specific RBD was selected that facilitated transmission to humans. In humans, the epidemic RBD was selected. (B) Direct bat-human paradigm. Transmission from bats to humans occurred without an intermediate host. Within the human population, selection for many RBDs resulted in the propagation of both the epidemic RBD and other closely related RBDs that could circulate within the civet population, maintaining an animal reservoir for continued viral persistence.
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