SARS-CoV and emergent coronaviruses: viral determinants of interspecies transmission

Abstract

Most new emerging viruses are derived from strains circulating in zoonotic reservoirs. Coronaviruses, which had an established potential for cross-species transmission within domesticated animals, suddenly became relevant with the unexpected emergence of the highly pathogenic human SARS-CoV strain from zoonotic reservoirs in 2002. SARS-CoV infected approximately 8000 people worldwide before public health measures halted the epidemic. Supported by robust time-ordered sequence variation, structural biology, well-characterized patient pools, and biological data, the emergence of SARS-CoV represents one of the best-studied natural models of viral disease emergence from zoonotic sources. This review article summarizes previous and more recent advances into the molecular and structural characteristics, with particular emphasis on host–receptor interactions, that drove this remarkable virus disease outbreak in human populations.

Figure 1

Spike phylogeny of representative CoVs and models of SARS-CoV emergence. (a) The Spike peptide sequence of 40 representative CoVs demonstrates that CoVs make up three distinct groups named alpha, beta, and gamma. These names replaced the former group 1, 2, and 3 designation, respectively. Classical subgroup clusters are marked as 2a–2d for the beta CoVs and 1a and 1b for the alpha CoVs. The tree was generated via Maximum Likelihood using the PhyML package. Major branch labels represent bootstraps that were greater than 70. SCoV: SARS-CoV; BtSCoV: bat SARS-like CoV; BtCoV, ZBCoV, and ARCoV: bat CoVs; HCoV: human; FCoV and FIPV: feline CoVs; BCoV: bovine; IBV: avian; PHEV, TGEV, PRV, PEDV: porcine CoVs; and MHV: murine hepatitis virus. (b) Competing models of SARS-CoV emergence. Early data suggested that SARS-CoV initially jumped from the zoonotic reservoir, bats, to palm civets, followed by a second jump from civets to humans (blue arrow). More recent phylogenetic and receptor analysis studies suggest a direct emergence from bats to humans, with subsequent cross-transmission between humans and civets (red arrow).

Figure 2

Sequence changes over the SARS-CoV epidemic. Shown here are the most significant changes important for transition of SARS from civet to early, middle and late phases of epidemic strains. Mutations indicative of lineages that were not likely to have contributed to the expansion to other phases have been removed. All other positions in the genome are identical.

Figure 3

Crystal structures of coronavirus receptor binding domains (RBDs) complexed with their receptors. To date, the crystal structures of three coronavirus Spike RBD–receptor complexes have been solved: (a) the RBDs of SARS complexed with human ACE2 (pdb 2AJF) [73], (b) NL63 complexed with human ACE2 (3KBH) [71^••], and (c) MHV complexed with murine CEACAM11a (3R4D) [43].

Figure 4

Experimental evolution at the SARS S glycoprotein RBD–ligand interface. The SARS RBD is heterogeneous and includes defined sequence variation at specific residues that engage the ACE2 receptor from different species (Parts 1 and 2). Bioinformatics can be used to predict and then test the impact of targeted mutations on variant virus–receptor interactions. Iterative rounds of mutation driven selection are also possible using recombinant viruses encoding targeted mutations and variant ACE2 receptors for docking and entry. The model allows a deep structural understanding of the potential pathways and molecular mechanisms that govern cross-species transmission and pathogenesis. The biological impact of host shifting on antigenicity can be predicted using structural models of antibody–RBD interfaces, and then studied using a panel of well characterized human and mouse monoclonal antibodies targeting the different SARS-CoV RBD domains (Part 3). In parallel, neutralizing monoclonal antibodies can be used to select for escape mutations (Part 4), allowing for iterative rounds of prediction and testing on how these mutations impact host range and ACE2 recognition.