Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease

Abstract

The source of the severe acute respiratory syndrome (SARS) epidemic was traced to wildlife market civets and ultimately to bats. Subsequent hunting for novel coronaviruses (CoVs) led to the discovery of two additional human and over 40 animal CoVs, including the prototype lineage C betacoronaviruses, Tylonycteris bat CoV HKU4 and Pipistrellus bat CoV HKU5; these are phylogenetically closely related to the Middle East respiratory syndrome (MERS) CoV, which has affected more than 1,000 patients with over 35% fatality since its emergence in 2012. All primary cases of MERS are epidemiologically linked to the Middle East. Some of these patients had contacted camels which shed virus and/or had positive serology. Most secondary cases are related to health care-associated clusters. The disease is especially severe in elderly men with comorbidities. Clinical severity may be related to MERS-CoV's ability to infect a broad range of cells with DPP4 expression, evade the host innate immune response, and induce cytokine dysregulation. Reverse transcription-PCR on respiratory and/or extrapulmonary specimens rapidly establishes diagnosis. Supportive treatment with extracorporeal membrane oxygenation and dialysis is often required in patients with organ failure. Antivirals with potent in vitro activities include neutralizing monoclonal antibodies, antiviral peptides, interferons, mycophenolic acid, and lopinavir. They should be evaluated in suitable animal models before clinical trials. Developing an effective camel MERS-CoV vaccine and implementing appropriate infection control measures may control the continuing epidemic.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

(A) Taxonomy of Coronaviridae according to the International Committee on Taxonomy of Viruses. (B) Phylogenetic tree of 50 coronaviruses with partial nucleotide sequences of RNA-dependent RNA polymerase. The tree was constructed by the neighbor-joining method using MEGA 5.0. The scale bar indicates the estimated number of substitutions per 20 nucleotides. Abbreviations (accession numbers): AntelopeCoV, sable antelope coronavirus (EF424621); BCoV, bovine coronavirus (NC_003045); BdCoV HKU22, bottlenose dolphin coronavirus HKU22 (KF793826); BuCoV HKU11, bulbul coronavirus HKU11 (FJ376619); BWCoV-SW1, beluga whale coronavirus SW1 (NC_010646); CMCoV HKU21, common-moorhen coronavirus HKU21 (NC_016996); DcCoV UAE-HKU23, dromedary camel coronavirus UAE-HKU23 (KF906251); ECoV, equine coronavirus (NC_010327); ErinaceousCoV, betacoronavirus Erinaceus/VMC/DEU/2012 (NC_022643); FIPV, feline infectious peritonitis virus (AY994055); HCoV-229E, human coronavirus 229E (NC_002645); HCoV-HKU1, human coronavirus HKU1 (NC_006577); HCoV-NL63, human coronavirus NL63 (NC_005831); HCoV-OC43, human coronavirus OC43 (NC_005147); Hi-BatCoV HKU10, Hipposideros bat coronavirus HKU10 (JQ989269); IBV-partridge, avian infectious bronchitis virus partridge isolate (AY646283); IBV-peafowl, avian infectious bronchitis virus peafowl isolate (AY641576); KSA-CAMEL-363, KSA-CAMEL-363 isolate of Middle East respiratory syndrome coronavirus (KJ713298); MERS-CoV, Middle East respiratory syndrome coronavirus (NC_019843.3); MHV, murine hepatitis virus (NC_001846); Mi-BatCoV 1A, Miniopterus bat coronavirus 1A (NC_010437); Mi-BatCoV 1B, Miniopterus bat coronavirus 1B (NC_010436); Mi-BatCoV HKU7, Miniopterus bat coronavirus HKU7 (DQ249226); Mi-BatCoV HKU8, Miniopterus bat coronavirus HKU8 (NC_010438); MRCoV HKU18, magpie robin coronavirus HKU18 (NC_016993); MunCoV HKU13, munia coronavirus HKU13 (FJ376622); My-BatCoV HKU6, Myotis bat coronavirus HKU6 (DQ249224); NeoCoV, coronavirus Neoromicia/PML-PHE1/RSA/2011 (KC869678); NHCoV HKU19, night heron coronavirus HKU19 (NC_016994); PEDV, porcine epidemic diarrhea virus (NC_003436); PHEV, porcine hemagglutinating encephalomyelitis virus (NC_007732); Pi-BatCoV-HKU5, Pipistrellus bat coronavirus HKU5 (NC_009020); PorCoV HKU15, porcine coronavirus HKU15 (NC_016990); PRCV, porcine respiratory coronavirus (DQ811787); RbCoV HKU14, rabbit coronavirus HKU14 (NC_017083); RCoV parker, rat coronavirus Parker (NC_012936); Rh-BatCoV HKU2, Rhinolophus bat coronavirus HKU2 (EF203064); Ro-BatCoV-HKU9, Rousettus bat coronavirusHKU9 (NC_009021); Ro-BatCoV HKU10, Rousettus bat coronavirus HKU10 (JQ989270); SARS-CoV, SARS coronavirus (NC_004718); SARSr-CiCoV, SARS-related palm civet coronavirus (AY304488); SARSr-Rh-BatCoV HKU3, SARS-related Rhinolophus bat coronavirus HKU3 (DQ022305); Sc-BatCoV 512, Scotophilus bat coronavirus 512 (NC_009657); SpCoV HKU17, sparrow coronavirus HKU17 (NC_016992); TCoV, turkey coronavirus (NC_010800); TGEV, transmissible gastroenteritis virus (DQ443743.1); ThCoV HKU12, thrush coronavirus HKU12 (FJ376621); Ty-BatCoV-HKU4, Tylonycteris bat coronavirus HKU4 (NC_009019); WECoV HKU16, white-eye coronavirus HKU16 (NC_016991); WiCoV HKU20, wigeon coronavirus HKU20 (NC_016995).

FIG 2

Genome arrangement of MERS-CoV, with emphasis on the clinical applications of the key nonstructural and structural genes and/or gene products. *, furin cleavage sites. Abbreviations: 3CLpro, 3C-like protease; AP, accessory protein; CP, cytoplasmic domain; E, envelope; FP, fusion peptide; Hel, helicase; HR, heptad repeat; IFN, interferon; M, membrane; mAb, monoclonal antibody; N, nucleocapsid; nsp, nonstructural protein; ORF, open reading frame; PLpro, papain-like protease; RBD, receptor-binding domain; RdRp, polymerase; RT-RPA; reverse transcription isothermal recombinase polymerase amplification; S, spike; SP, signal peptide; TM, transmembrane domain.

FIG 3

Candidate antiviral agents for MERS-CoV in relation to the viral replication cycle. + and −, positive- and negative-strand RNA, respectively. Abbreviations: AKT, protein kinase B; AP, accessory protein; Cyps, cyclophilins; dec-RVKR-CMK, decanoyl-RVKR-chloromethylketone; DPP4, dipeptidyl peptidase 4; E, envelope; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum Golgi intermediate compartment; ERK, extracellular signal-regulated kinases; HR2P, heptad repeat 2 peptide; IFN, interferon; M, membrane; mAb, monoclonal antibody; MAPK, mitogen-activated protein kinases; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin; N, nucleocapsid; NFAT, nuclear factor of activated T cells; nsp, nonstructural protein; ORF, open reading frame; PI3K, phosphatidylinositide 3-kinases; S, spike; TMPRSS2, transmembrane protease serine protease 2.

FIG 4

Phylogenetic tree of the complete genomes of 27 representative human (black) and camel (red) MERS-CoV strains rooted by NeoCoV (KC869678.4). The tree was constructed by the neighbor-joining method using MEGA 5.0. The scale bar indicates the estimated number of substitutions per 2,000 nucleotides.