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Review
. 2015 Aug 28;47(8):e181.
doi: 10.1038/emm.2015.76.

Middle East respiratory syndrome coronavirus: transmission, virology and therapeutic targeting to aid in outbreak control

Affiliations
Review

Middle East respiratory syndrome coronavirus: transmission, virology and therapeutic targeting to aid in outbreak control

Prasannavenkatesh Durai et al. Exp Mol Med. .

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) causes high fever, cough, acute respiratory tract infection and multiorgan dysfunction that may eventually lead to the death of the infected individuals. MERS-CoV is thought to be transmitted to humans through dromedary camels. The occurrence of the virus was first reported in the Middle East and it subsequently spread to several parts of the world. Since 2012, about 1368 infections, including ~487 deaths, have been reported worldwide. Notably, the recent human-to-human 'superspreading' of MERS-CoV in hospitals in South Korea has raised a major global health concern. The fatality rate in MERS-CoV infection is four times higher compared with that of the closely related severe acute respiratory syndrome coronavirus infection. Currently, no drug has been clinically approved to control MERS-CoV infection. In this study, we highlight the potential drug targets that can be used to develop anti-MERS-CoV therapeutics.

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Figures

Figure 1
Figure 1
Global distribution map of Middle East respiratory syndrome coronavirus (MERS-CoV). Individuals in 26 countries have been infected by MERS-CoV. The infographic was generated based on MERS-CoV updates released on 7 July 2015 by World Health Organization. (WHO; http://www.who.int/csr/disease/coronavirus_infections/risk-assessment-7july2015/en/).
Figure 2
Figure 2
Phylogenetic analysis of the complete Middle East respiratory syndrome coronavirus (MERS-CoV) genomes using the maximum-likelihood method based on Tamura-Nei model implemented in MEGA5. The analysis involved 14 (human and camel) complete MERS-CoV genomes selected from different countries and their accession numbers are given at the end of each branch. The tree was rooted using the Egyptian camel sequence as the most divergent. CH, China, EG, Egypt; FR, France; KR, Republic of Korea; OM, Oman; QT, Qatar; SA, Saudi Arabia, UAE, United Arab Emirates; UK, United Kingdom; US: United States.
Figure 3
Figure 3
Schematic of the replication cycle of Middle East respiratory syndrome coronavirus (MERS-CoV). MERS-CoV binds to dipeptidyl peptidase 4 (DPP4) on the host cell through its receptor-binding domain (RBD) in the S1 subunit of the spike (S) glycoprotein, which leads to virus–cell fusion and the release of genomic RNA into the cytoplasm. Initially open reading frame 1a (ORF1a) and ORF1b are translated into polyproteins, polyprotein 1a (pp1a) and pp1ab, respectively, which are cleaved by the virus-encoded proteases papain-like protease (PLpro) and 3C-like protease (3CLpro) into 16 mature nonstructural proteins (nsps). The proteins involved in replication and transcription are gathered into replication-transcription complexes (RTCs) that associate with double-membrane vesicles (DMVs) derived from the endoplasmic reticulum (ER). The genomic RNA contains adenylate uridylate (AU)-rich sequences called transcription regulation sequences (TRSs). If the TRSs are recognized by RTCs, then RNA of subgenomic length for transcription will be generated, otherwise a full-length template RNA of genomic length for replication will be synthesized. The newly produced genomic RNAs are encapsidated in the nucleocapsid (N) proteins in the cytoplasm and then transported to the ER–Golgi intermediate compartment (ERGIC) for further assembly. The S, membrane (M) and envelope (E) proteins are inserted into the membrane of the rough ER (RER), from where they are transported to the ERGIC to interact with the RNA-encapsidated N proteins and assemble into viral particles. The budded vesicles containing mature viral particles are then transported to the cell surface for release after maturation in the Golgi bodies. Double-stranded RNAs (dsRNAs) are partially generated during viral replication. The 4a competes with Toll-like receptor 3 (TLR3) and retinoic acid-inducible gene I product (RIG-I)-like helicases (RIG-I and melanoma differentiation-associated protein 5 (MDA5)) to bind to dsRNAs and evades the host immune response.

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