From SARS to MERS, Thrusting Coronaviruses into the Spotlight

Abstract

Coronaviruses (CoVs) have formerly been regarded as relatively harmless respiratory pathogens to humans. However, two outbreaks of severe respiratory tract infection, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), as a result of zoonotic CoVs crossing the species barrier, caused high pathogenicity and mortality rates in human populations. This brought CoVs global attention and highlighted the importance of controlling infectious pathogens at international borders. In this review, we focus on our current understanding of the epidemiology, pathogenesis, prevention, and treatment of SARS-CoV and MERS-CoV, as well as provides details on the pivotal structure and function of the spike proteins (S proteins) on the surface of each of these viruses. For building up more suitable animal models, we compare the current animal models recapitulating pathogenesis and summarize the potential role of host receptors contributing to diverse host affinity in various species. We outline the research still needed to fully elucidate the pathogenic mechanism of these viruses, to construct reproducible animal models, and ultimately develop countermeasures to conquer not only SARS-CoV and MERS-CoV, but also these emerging coronaviral diseases.

Keywords: MERS-CoV; SARS-CoV; animal model; coronaviruses; prevention and treatment; spike proteins.

Figure 1

Schematic representation of the genome organization and functional domains of S protein for SARS-CoV and MERS-CoV. The single-stranded RNA genomes of SARS-CoV and MERS-CoV encode two large genes, the ORF1a and ORF1b genes, which encode 16 non-structural proteins (nsp1–nsp16) that are highly conserved throughout coronaviruses. The structural genes encode the structural proteins, spike (S), envelope (E), membrane (M), and nucleocapsid (N), which are common features to all coronaviruses. The accessory genes (shades of green) are unique to different coronaviruses in terms of number, genomic organization, sequence, and function. The structure of each S protein is shown beneath the genome organization. The S protein mainly contains the S1 and S2 subunits. The residue numbers in each region represent their positions in the S protein of SARS and MERS, respectively. The S1/S2 cleavage sites are highlighted by dotted lines. SARS-CoV, severe acute respiratory syndrome coronavirus; MERS-CoV, Middle East respiratory syndrome coronavirus; CP, cytoplasm domain; FP, fusion peptide; HR, heptad repeat; RBD, receptor-binding domain; RBM, receptor-binding motif; SP, signal peptide; TM, transmembrane domain.

Figure 2

The life cycle of SARS-CoV and MERS-CoV in host cells. SARS-CoV and MERS-CoV enter target cells through an endosomal pathway. The S proteins of SARS and MERS bind to cellular receptor angiotensin-converting enzyme 2 (ACE2) and cellular receptor dipeptidyl peptidase 4 (DPP4), respectively. Following entry of the virus into the host cell, the viral RNA is unveiled in the cytoplasm. ORF1a and ORF1ab are translated to produce pp1a and pp1ab polyproteins, which are cleaved by the proteases that are encoded by ORF1a to yield 16 non-structural proteins that form the RNA replicase–transcriptase complex. This complex drives the production of negative-sense RNAs [(−) RNA] through both replication and transcription. During replication, full-length (−) RNA copies of the genome are produced and used as templates for full-length (+) RNA genomes. During transcription, a subset of 7–9 sub-genomic RNAs, including those encoding all structural proteins, is produced through discontinuous transcription. Although the different sub-genomic mRNAs may contain several open reading frames (ORFs), only the first ORF (that closest to the 5′ end) is translated. Viral nucleocapsids are assembled from genomic RNA and N protein in the cytoplasm, followed by budding into the lumen of the ERGIC (endoplasmic reticulum (ER)–Golgi intermediate compartment). Virions are then released from the infected cell through exocytosis. SARS-CoV, severe acute respiratory syndrome coronavirus; MERS-CoV, Middle East respiratory syndrome coronavirus; S, spike; E, envelope; M, membrane; N, nucleocapsid.