SARS and MERS: recent insights into emerging coronaviruses

Emmie de Wit, Neeltje van Doremalen, Darryl Falzarano, Vincent J Munster, Emmie de Wit, Neeltje van Doremalen, Darryl Falzarano, Vincent J Munster

Abstract

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 marked the second introduction of a highly pathogenic coronavirus into the human population in the twenty-first century. The continuing introductions of MERS-CoV from dromedary camels, the subsequent travel-related viral spread, the unprecedented nosocomial outbreaks and the high case-fatality rates highlight the need for prophylactic and therapeutic measures. Scientific advancements since the 2002-2003 severe acute respiratory syndrome coronavirus (SARS-CoV) pandemic allowed for rapid progress in our understanding of the epidemiology and pathogenesis of MERS-CoV and the development of therapeutics. In this Review, we detail our present understanding of the transmission and pathogenesis of SARS-CoV and MERS-CoV, and discuss the current state of development of measures to combat emerging coronaviruses.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1. SARS-CoV and MERS-CoV structure and…
Figure 1. SARS-CoV and MERS-CoV structure and replication.
a | The single-stranded RNA (ssRNA) genomes of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) encode two large polyproteins, pp1a and pp1ab, which are proteolytically cleaved into 16 non-structural proteins (nsps), including papain-like protease (PLpro), 3C-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), helicase (Hel) and exonuclease (ExoN). An additional 9–12 ORFs are encoded through the transcription of a nested set of subgenomic RNAs. SARS-CoV and MERS-CoV form spherical particles that consist of four structural proteins. The envelope glycoprotein spike (S) forms a layer of glycoproteins that protrude from the envelope. Two additional transmembrane glycoproteins are incorporated in the virion: envelope (E) and membrane (M). Inside the viral envelope resides the helical nucleocapsid, which consists of the viral positive-sense RNA ((+)RNA) genome encapsidated by protein nucleocapsid (N). b | Following entry of the virus into the host cell, the viral RNA is uncoated in the cytoplasm. ORF1a and ORF1ab are translated to produce pp1a and pp1ab, which are cleaved by the proteases that are encoded by ORF1a to yield 16 nsps that form the RNA replicase–transcriptase complex. This complex localizes to modified intracellular membranes that are derived from the rough endoplasmic reticulum (ER) in the perinuclear region, and it drives the production of negative-sense RNAs ((−)RNAs) 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 subgenomic RNAs, including those encoding all structural proteins, is produced through discontinuous transcription. In this process, subgenomic (−)RNAs are synthesized by combining varying lengths of the 3′ end of the genome with the 5′ leader sequence necessary for translation. These subgenomic (−)RNAs are then transcribed into subgenomic (+)mRNAs. Although the different subgenomic mRNAs may contain several ORFs, only the first ORF (that closest to the 5′ end) is translated. The resulting structural proteins are assembled into the nucleocapsid and viral envelope at the ER–Golgi intermediate compartment (ERGIC), followed by release of the nascent virion from the infected cell. PowerPoint slide
Figure 2. The emergence of SARS-CoV and…
Figure 2. The emergence of SARS-CoV and MERS-CoV.
Bats harbour a wide range of coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV)-like and Middle East respiratory syndrome coronavirus (MERS-CoV)-like viruses. SARS-CoV crossed the species barrier into masked palm civets and other animals in live-animal markets in China; genetic analysis suggests that this occurred in late 2002. Several people in close proximity to palm civets became infected with SARS-CoV. A MERS-CoV ancestral virus crossed the species barrier into dromedary camels; serological evidence suggests that this happened more than 30 years ago. Abundant circulation of MERS-CoV in dromedary camels results in frequent zoonotic transmission of this virus. SARS-CoV and MERS-CoV spread between humans mainly through nosocomial transmission, which results in the infection of health care workers and patients at a higher frequency than infection of their relatives. PowerPoint slide
Figure 3. Evasion of the innate immune…
Figure 3. Evasion of the innate immune response by SARS-CoV and MERS-CoV.
a | The innate immune response is activated by the detection of viral pathogen-associated molecular patterns (PAMPs), such as double-stranded RNA (dsRNA) or uncapped mRNA. This occurs via host pattern recognition receptors (PRRs), such as retinoic acid-inducible gene I protein (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), potentially via dsRNA-binding partners such as IFN-inducible dsRNA-dependent protein kinase activator A (PRKRA). Following PRR-mediated detection of a PAMP, the resulting interaction of PRRs with mitochondrial antiviral-signalling protein (MAVS) activates nuclear factor-κB (NF-κB) through a signalling cascade involving several kinases. Activated NF-κB translocates to the nucleus, where it induces the transcription of pro-inflammatory cytokines. The kinases also phosphorylate (P) IFN-regulatory factor 3 (IRF3) and IRF7, which form homodimers and heterodimers and enter the nucleus to initiate the transcription of type I interferons (type I IFNs). Both severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have developed mechanisms to interfere with these signalling pathways, as shown; these subversion strategies involve both structural proteins (membrane (M) and nucleocapsid (N)) and non-structural proteins (nsp1, nsp3b, nsp4a, nsp4b, nsp5, nsp6 and papain-like protease (PLpro); indicated in the figure by just their nsp numbers and letters). b | Binding of type I IFNs to their dimeric receptor, IFNα/β receptor (IFNAR), activates the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling pathway, in which JAK1 and TYK2 kinases phosphorylate STAT1 and STAT2, which form complexes with IRF9. These complexes move into the nucleus to initiate the transcription of IFN-stimulated genes (ISGs) under the control of promoters that contain an IFN-stimulated response element (ISRE). Collectively, the expression of cytokines, IFNs and ISGs establishes an antiviral innate immune response that limits viral replication in infected and in neighbouring cells. Again, viral proteins have been shown to inhibit these host signalling pathways to evade this immune response. IκBα, NF-κB inhibitor-α. PowerPoint slide

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