Middle East respiratory syndrome

Abstract

The Middle East respiratory syndrome coronavirus (MERS-CoV) is a lethal zoonotic pathogen that was first identified in humans in Saudi Arabia and Jordan in 2012. Intermittent sporadic cases, community clusters, and nosocomial outbreaks of MERS-CoV continue to occur. Between April 2012 and December 2019, 2499 laboratory-confirmed cases of MERS-CoV infection, including 858 deaths (34·3% mortality) were reported from 27 countries to WHO, the majority of which were reported by Saudi Arabia (2106 cases, 780 deaths). Large outbreaks of human-to-human transmission have occurred, the largest in Riyadh and Jeddah in 2014 and in South Korea in 2015. MERS-CoV remains a high-threat pathogen identified by WHO as a priority pathogen because it causes severe disease that has a high mortality rate, epidemic potential, and no medical countermeasures. This Seminar provides an update on the current knowledge and perspectives on MERS epidemiology, virology, mode of transmission, pathogenesis, diagnosis, clinical features, management, infection control, development of new therapeutics and vaccines, and highlights unanswered questions and priorities for research, improved management, and prevention.

Figure 1

MERS-CoV structure, genome organisation, and replication MERS-CoV encodes a large replicase-transcriptase polyprotein (rep1A and rep1B), which is processed into 16 non-structural proteins (nsp). These proteins are required for the formation of the replicase-transcription complex, for cleavage of the polyprotein, and for immune evasion. Structural proteins (spike [S], envelope [E], membrane [M], and nucleocapsid [N]) and accessory proteins (ORFs 3, 4a, 4b, 5, 8b) are encoded in the end third of the 3' end of the genome of the genome. MERS-CoV binds to its cellular receptor DPP4 via the S protein, which is processed by host proteases to expose a fusion peptide. The viral genome is then released into the cytoplasm, where it is translated on host ribosomes into rep1A and rep1B proteins. The polyprotein is cleaved by two viral-encoded proteases, encoded by nsp3 and nsp5. Proteins involved in genome and subgenome replication and transcription include nsp12 (the RNA-dependent RNA polymerase [RdRP]) and two associated proteins, nsp7 and nsp8. Nsp13 (a helicase), nsp14 (which encodes an N7 methyltransferase and ExoN, a protein required for genome fidelity), and nsp16 (a 2'-O methyltransferase) are also necessary for optimal genomic and subgenomic RNA synthesis. MERS-CoV transcription involves the synthesis of subgenomic RNAs, which encode the structural and accessory proteins located at the 3' end of the genome. Subgenomic and genomic RNAs are co-terminal, sharing the same 5' leader and 3' sequences. Subgenomic RNAs code for structural and accessory proteins (ORF3, 4a, 4b, 5, and 8b). ORF8b is encoded within the N gene (marked with purple lines). These accessory proteins are believed to have immunoevasive properties, but are not essential for replication, and are variably deleted in human and camel virus isolates., , Genomic replication occurs on membrane structures such as double membrane vesicles (DMVs), convoluted membranes (CM), and vesicle packets (VP), which are merged DMV that have been formed from the rough endoplasmic reticulum (RER) by the combined action of nsp3, nsp4, and nsp6 (lower right). After synthesis on replicase-transcription complexes, RNA is encapsidated by the N protein and transported to the ERGIC (endoplasmic reticulum–Golgi compartment), where budding into membranes containing the S, E, and M proteins occurs before release from the cell. 3CLPro=chymotrypsin-like protease. ExoN=exonuclease. MERS-CoV=Middle East respiratory syndrome coronavirus. MTase=methyltransferase. NendoU=nidoviral uridylate-specific endoribonuclease. NF-κB=nuclear factor κ-light-chain-enhancer of activated B cells. NTPase=nucleoside-triphosphatase. pp1a=polyprotein 1a. PLPro=papain-like protease.

Figure 2

Geographical distribution of reported human infections of MERS-CoV Cases reported up to and including Dec 31, 2019. MERS-CoV=Middle East respiratory syndrome coronavirus. Reproduced from Dr Mamunur R Malik, WHO Regional Office for the Eastern Mediterranean.

Figure 3

Global MERS reported to WHO by week, 2012–19 Reproduced from WHO website, by permission of Dr Mamunur R Malik, WHO Regional Office for the Eastern Mediterranean. MERS=Middle East respiratory syndrome.

Figure 4

Epidemiological, clinical, and laboratory features of MERS ALT=alanine aminotransferase. AST=asparate aminotransferase. MERS-CoV=Middle East respiratory syndrome coronavirus.

Figure 5

Chest imaging abnormalities in patients with Middle East respiratory syndrome (A) Chest x-rays showing bilateral extensive diffuse and focal opacities. (B) Chest CT scan showing bilateral extensive ground-glass reticulonodular shadowing with bronchiolar wall thickening.