2017 Middle East respiratory syndrome (MERS) coronavirus and dromedaries

2017·0.48 MB·English

TheVeterinaryJournal220(2017)75–79
ContentslistsavailableatScienceDirect
The Veterinary Journal
journal homepage: www.elsevier.com/locate/tvjl
Review
Middle East respiratory syndrome (MERS) coronavirus and
dromedaries
UlrichWernerya,*,SusannaK.P.Laub,PatrickC.Y.Woob
aCentralVeterinaryResearchLaboratory,Dubai,UnitedArabEmirates
bDepartmentofMicrobiology,UniversityofHongKong,HongKong,China
A R T I C L E I N F O A B S T R A C T
Articlehistory: MiddleEastRespiratorySyndrome(MERS)isazoonoticviraldiseasethatcanbetransmittedfromdrom-
Accepted28December2016 edariestohumanbeings.Morethan1500casesofMERShavebeenreportedinhumanbeingstodate.
AlthoughMERShasbeenassociatedwith30%casefatalityinhumanbeings,MERScoronavirus(MERS-
Keywords: CoV)infectionindromedariesisusuallyasymptomatic.Inrarecases,dromedariesmaydevelopmild
MiddleEastrespiratorysyndrome(MERS) respiratorysigns.NoMERS-CoVorantibodiesagainstthevirushavebeendetectedincamelidsotherthan
Coronavirus
dromedaries.MERS-CoVismainlyacquiredindromedarieswhentheyarelessthan1yearofage,and
Dromedary
theproportionofseropositivityincreaseswithagetoaseroprevalenceof100%inadultdromedaries.
Diagnosis
LaboratorydiagnosisofMERS-CoVinfectionindromedariescanbeachievedthroughvirusisolationusing
Verocells,RNAdetectionbyreal-timequantitativereversetranscriptase-PCRandantigendetectionusing
respiratoryspecimensorserum.Rapidnucleocapsidantigendetectionusingalateralflowplatformallows
efficientscreeningofdromedariescarryingMERS-CoV.InadditiontoMERS-CoV,whichisalineageC
virusintheBetacoronavirus(betaCoV)genus,alineageBbetaCoVandavirusintheAlphacoronavirus
(alphaCoV)genushavebeendetectedindromedaries.DromedaryCoVUAE-HKU23iscloselyrelatedto
humanCoVOC43,whereasthealphaCoVhasnotbeendetectedinhumanbeingstodate.
©2017PublishedbyElsevierLtd.
Introduction quent human-to-human transmission result in MERS in human
beings,manyofwhomdevelopseverelowerrespiratorytractin-
SincetheemergenceofMiddleEastrespiratorysyndrome(MERS) fections,withrenalfailureinsomecases(Arabietal.,2014;Saad
in2012,morethan1500humancaseshavebeenreported,witha etal.,2014).Incontrasttohumaninfection,MERS-CoVcausesno
casefatalityof~30%(WorldHealthOrganization(WHO),2016).The ormilddiseaseindromedaries.Inthisarticle,ourcurrentunder-
causative agent of MERS has been confirmed to be a novel standingofMERS-CoVinfectionindromedariesisreviewedandthe
coronavirus(CoV),namedMERS-CoV(vanBoheemenetal.,2012; presenceofotherCoVsindromedariesisalsodiscussed.
Zaki et al., 2012). CoVs are positive-sense single-stranded RNA
viruseswithgenomesizeof ~30kb.Theyhavethecharacteristic
MERS-CoVinfectionindromedaries
crown-shapedappearanceonelectronmicroscopicexamination.
CoVsareclassifiedintofourgenera,Alphacoronavirus,Betacoronavirus
Morethan20MERS-CoVisolateshavebeenrecoveredfromnasal
(withfourlineages),GammacoronavirusandDeltacoronavirus(Woo
swabsfromyoungdromedariesfromdifferentfarmsinDubaiover
etal.,2012).MERS-CoVbelongstolineageCofBetacoronavirus(Fig.1)
thelast2yearsattheCentralVeterinaryResearchLaboratory.These
(vanBoheemenetal.,2012).
animalsdiedfromdiseasesunrelatedtoMERS,suchasselenium
Subsequentinvestigationshaveshownthatdromedaryorone
deficiency,cryptosporidiosis,salmonellosis,Escherichiacolisepti-
humpedcamels(Camelusdromedarius)aresofartheonlyreser-
caemiaandClostridiumperfringensAenterotoxaemia.Nonehadnasal
voirofMERS-CoV(Alagailietal.,2014;Chuetal.,2014;Wernery
dischargeanditisbelievedthatthevirusisolationwasincidental
et al., 2015a, 2015b; Sabir et al., 2016). Adult dromedaries have
tothedeathofthedromedaries.Histopathologicalinvestigations
almost100%seropositivityagainstMERS-CoVwhilethevirusisfound
didnotshowanylesionsconsistentwithvirusinfection.
mainlyindromedarycalves(Alagailietal.,2014;Werneryetal.,
However,experimentalinfectionsofdromedarieswithMERS-
2015b). Camel-to-human transmission of MERS-CoV and subse-
CoVintheUSAandSpainpredominantlyinducedrespiratorytract
diseasewithnoormildclinicalrespiratorysigns(Adneyetal.,2014;
Haagmans et al., 2016). The experimentally infected animals
demonstratedmoderaterhinitis,withnasaldischarge,tracheitis
* Correspondingauthor.
E-mailaddress:[email protected](U.Wernery). and bronchitis, but no involvement of the alveolar tissue. The
http://dx.doi.org/10.1016/j.tvjl.2016.12.020
1090-0233/©2017PublishedbyElsevierLtd.
76 U.Werneryetal./TheVeterinaryJournal220(2017)75–79
alsoperformedinalpacas,withsimilarresults(Adneyetal.,2016).
Experimentallyinfectedalpacastransmittedthevirustotwoofthree
contactanimals.Experimentallyinfectedanimalswereprotected
againstreinfection70dayslaterandthoseinfectedbycontactwere
onlypartiallyprotected.
LaboratorydiagnosisofMERS-CoVinfectionindromedaries
DetectionofMERS-CoVindromedariesisperformedtounder-
standtheepidemiologyandevolutionarydynamicsofthevirusand
toreducetheriskofhumantransmission.MERS-CoVwasfirstiso-
latedfromahumanpatientsufferingfromfatallowerrespiratory
tractinfectionandacuterenalfailureinSaudiArabiain2012(van
Boheemenetal.,2012;Zakietal.,2012).Sincethen,thevirushas
been isolated from both human beings and dromedaries. Al-
thoughVerocellsareusuallythecelllineusedinclinicallaboratories,
the virus can be propagated in a variety of human and non-
humancelllines,whichmayhaveimplicationsforitstissuetropism
andthehighfatalityassociatedwithMERS(Chanetal.,2013;Eckerle
etal.,2014;Zhouetal.,2015).
MERS-CoVhasbeenisolatedfromnasalswabsofyoungdrom-
edaries(Wernery,2014;Werneryetal.,2015a;Binetal.,2016),but
hasnotbeenrecoveredfromadultdromedaries.Overthelast3years,
severalhundredsampleshavebeentestedattheCentralVeterinary
ResearchLaboratory,Dubai,forthepresenceofMERS-CoVatpost-
mortemexaminationfromserologicallypositiveMERS-CoVadult
dromedariesgreaterthan4yearsofage.Mostofthedromedaries
camefromfarmswhereMERS-CoVwasisolatedfromthenasalcavity
ofyounganimals.However,noMERS-CoVhasbeenrecoveredfrom
anysamplesfromadultdromedaries,includingnasalswabs,tonsils,
lungs,intestinallymphnodes,mammarylymphnodesandmilk.
Althoughisolatingtheviruswillbeusefulforfurtherresearch,
suchasantiviralsusceptibilitytesting,diagnosisofMERS-CoVin-
Fig.1. PhylogeneticanalysisofRNA-dependent-RNA-polymerase(RdRp)ofMiddle fection in dromedaries is mainly achieved through nucleic acid
Eastrespiratorysyndrome(MERS)coronavirus(MERS-CoV)andothercoronaviruses.
detection.Amongallthenucleicaciddetectiontechnologies,the
Thetreewasconstructedbyneighbour-joiningmethodusingmaximumcompos-
itelikelihoodsubstitutionmodelwithbootstrapvaluescalculatedfrom1000trees. mostwidelyusedforMERS-CoVdiagnosisisreal-timequantita-
ViruslistandGenBankaccessionnumbersasfollow:HCoV-NL63,humanCoVNL63 tivereversetranscriptase(RT)-PCR(RT-qPCR),usinganumberof
(NC_005831);HCoV-229E(NC_002645);RhBatCoVHKU2,rhinolophusbatCoVHKU2 possibletargets,includingtheRNA-dependentRNApolymerase,the
(EF203064);Sc-BatCoV-512,scotophilusbatCoV512(NC_009657);PEDV,porcine
regionupstreamtotheenvelopegene,orthenucleocapsidgene
epidemicdiarrhoeavirus(NC_003436);FIPV,felineinfectiousperitonitisvirus
(Cormanetal.,2012a,2012b).RT-qPCRhashighsensitivityandspeci-
(AY994055);PRCV,porcinerespiratoryCoV(DQ811787);TGEV,transmissiblegas-
troenteritisvirus(NC_002306);IBV,infectiousbronchitisvirus(NC_001451);BdCoV ficityfordiagnosisofMERS-CoVinfection.
HKU22,bottlenosedolphinCoVHKU22(KF793826);BWCoV-SW1,BelugawhaleCoV RapiddiagnosisofMERS-CoVinfectionsindromedariescanalso
SW1(NC_010646);GiCoV,giraffeCoV(EF424622);SACoV,sableantelopeCoV beachievedbydirectantigendetectionassays.In2015,wepub-
(EF424621);BCoV,bovineCoV(NC_003045);DcCoVHKU23,dromedarycamelCoV
lishedamonoclonalantibody-basedELISAforthedetectionofthe
HKU23(KF906251);PHEV,porcinehaemagglutinatingencephalomyelitisvirus
(NC_007732);HCoV-OC43,humanCoVOC43(NC_005147);RbCoVHKU14,rabbit nucleocapsidantigenofMERS-CoVinrespiratorysamples,withhigh
CoVHKU14(JN874559);ChRCoVHKU24,ChinaRattusCoVHKU24(KM349742);MHV, sensitivityandspecificity(Chenetal.,2015).Recently,wehaveused
murinehepatitisvirus(NC_001846);HCoV-HKU1,humanCoVHKU1(NC_006577); alateralflowimmunoassayplatformforrapiddetectionofnucleo-
humanMERS-CoV,humanMiddleEastrespiratorysyndromeCoV(JX869059);Camel
capsidantigeninrespiratorysamplesof dromedaries;thishasa
MER-CoV,CamelMiddleEastrespiratorysyndromeCoV(KT751244);NeoCoV,
sensitivityof~80%andaspecificityof100%whencomparedtoRT-
NeoromiciaCoV(KC869678);BatCoV-SC2013,BatcoronavirusSC2013(KJ473821);
Ty-BatCoVHKU4,tylonycterisbatCoVHKU4(NC_009019);Pi-BatCoVHKU5, qPCR(Chenetal.,2016).Thistechnologyhasenabledtheon-site
pipistrellusbatCoVHKU5(NC_009020);EriCoV,ErinaceusCoV(KC545383);Civet screeningofalargenumberofdromedariesinashortperiodoftime.
SARSCoV,SARS-relatedpalmcivetCoV(AY304488);humanSARS-CoV,severeacute Italsoavoidstheuseofexpensiveequipmentanddoesnotrequire
respiratorysyndrome-associatedhumanCoV(NC_004718);badgerSARS-CoV,SARS-
expertiseinmoleculardiagnostics.
relatedChineseferretbadgerCoV(AY545919);SARSr-Rs-BatCoV-HKU3,SARS-
relatedrhinolophusbatCoVHKU3(DQ022305);Ro-BatCoVHKU9,rousettusbatCoV
HKU9(NC_009021);NhCoVHKU19,night-heronCoVHKU19(NC_016994);WiCoV Seroepidemiology
HKU20,wigeonCoVHKU20(NC_016995);CmCoVHKU21,common-moorhenCoV
HKU21(NC_016996);BuCoVHKU11,bulbulCoVHKU11(FJ376619);ThCoVHKU12,
ThefirstevidenceofdromedariesbeingthereservoirofMERS-
thrushCoVHKU12(FJ376621);WECoVHKU16,white-eyeCoVHKU16(NC_016991);
CoV came from serological studies. High levels of MERS-CoV
MunCoVHKU13,muniaCoVHKU13(FJ376622);MRCoVHKU18,magpie-robinCoV
HKU18(NC_016993);PorCoVHKU15,porcineCoVHKU15(NC_016990);SpCoV antibodieshavebeenobservedindromedariesintheMiddleEast
HKU17,sparrowCoVHKU17(NC_016992). andAfrica(Reuskenetal.,2013;Cormanetal.,2014a;Hemidaetal.,
2014;Meyeretal.,2014;Mulleretal.,2014;MackayandArden,
2015).Serologicalfollow-upofdromedarydamsandtheircalves
dromedarieswereinfectedwithhighdosesofMERS-CoVintrana- hasshowedatypicalpatternofjuvenileinfection.Maternalanti-
sally,i.e.1×10750%tissuecultureinfectiousdoses(TCID )inthe bodiesagainstMERS-CoVindromedarycalvesgenerallydisappear
50
study of Adney et al. (2014) and 5×106 TCID in the study of between4and8monthsofage,permittinginfectiontooccurduring
50
Haagmansetal.(2016).ExperimentalMERS-CoVinfectionswere theseronegativeperiod(Alagailietal.,2014;Binetal.,2016);young
U.Werneryetal./TheVeterinaryJournal220(2017)75–79 77
infecteddromedariesthendevelopantibodiesthatpersistforalong 2015).ItisworthwhilementioningthatnohumanMERS-CoVcases
time.However,inafewcases,MERS-CoVhasbeenisolatedatthe havebeenseenoncameldairyfarmsintheUnitedArabEmirates,
ageof20daysorevenatyounger,indicatingthatmaternalanti- even though the virus has been isolated regularly from drome-
bodiesarenotnecessarilyprotective.Sofar,thespecificsourceof darycalves.
infectionforyoungdromedariesisnotknown,althoughitislikely Transmission from dromedaries to human beings is presum-
to be from other dromedaries. Extensive investigations in other ablyuncommon,becausetheseroprevalenceinhumanbeingsislow,
animal species, including rodents, ticks, horses and small rumi- eveninpeopleinfrequentcontactwithdromedaries(Hemidaetal.,
nants,havenotdemonstratedotherreservoirsofinfectiontodate. 2015).Theremaybeseveralreasonsforthelowfrequencyoftrans-
missionfromcamelstohumanbeings.Onlyyoungdromedarieswith
Preventionandcontrol noorlowmaternalantibodiestoMERS-CoVaresusceptibletoin-
fectionandthevirusisshedonlyfor8days(Werneryetal.,2015b).
Protective experimental immunisations in dromedaries have Theseyoungdromedariesarerearedwiththeirmothersforayear
alreadystartedusingamodifiedvacciniavirusAnkara(MVA)vaccine andhavenoorverylittlecontactwithhumanbeings.Additional-
expressingtheMERS-CoVspikeprotein(Haagmansetal.,2016).Pre- ly, less than 1% of infected calves exhibit nasal discharge and
liminary data showed a significant reduction in excretion of thereforethequantityofvirusexcretedmaybelow.Anotherreason
infectiousvirusandviralRNAinsmallnumbersofvaccinatedand forthelowtransmissionrateislikelytobethelackexpressionof
challengeddromedariescomparedtocontrols.Protectioniscorre- theMERS-CoVreceptor-dipeptidylpeptidase4(DPP4)inthehuman
latedwiththepresenceof serumneutralisingantibodiesagainst upperrespiratorytract(Widagdoetal.,2016).Caremustbetaken
MERS-CoV.MVA-specificantibodiesthatcross-neutralisecamelpox whencamelcalveshavetobetreated.Inthesecases,caretakersand
virusareanotherveryimportantadvantageofthisvaccine,since veterinariansshouldwearprotectivegeartoavoidanytransmis-
outbreaksof camelpoxstilloccurindromedaries(Higginsetal., sionfromcamelcalvestohumanbeings.
1992). Another approach would be to add a MERS-CoV compo- In contrast to the monophylectic origin of SARS-CoV, MERS-
nenttothealreadyexistingattenuatedcamelpoxvaccineDucapox. CoV strains from human beings are polyphylectic as a result of
SinceDucapoxhasbeenusedintheMiddleEastformanyyears, multiplecamel-to-humantransmissionevents(Arabietal.,2014;
theacceptanceofsuchavaccinecanbeanticipated(Werneryetal., Lingetal.,2015).ThisimpliesthatMERS-CoVhasbeenpresentin
2014).However,itisimportantforthesuccessofavaccinetoadhere dromedariesformanydecades.Italsoprovidesanexplanationwhy
strictlytotheexacttimeofvaccination,sincethewindowofdis- MERShasnowpersistedformorethan3years,unlikeSARSwhich
appearanceofmaternalantibodiesandappearanceofantibodies disappearedrapidlyaftercivetswereremovedbyclosureofanimal
asaresultofinfectionisnarrow. marketsinSouthernChina.MERS-CoVislikelytocontinuetobea
threattohumanbeingsunlessvaccinesareavailable.
MERSasazoonoticdisease
CoronavirusesotherthanMERS-CoVincamelids
MERSisazoonoticviraldiseasethatcanbetransmittedfrom
dromedaries to human beings. Several groups have performed Coronavirusesarewidespreadandinfectabroadrangeofspecies.
seroepidemiologicalstudiesindifferentcamelspeciesinvarious AnalphaCoVhasbeenisolatedfromNewWorldcamelids(NWCs,
countriesandcontinents.Sofar,noantibodiestoMERS-CoVhave also known as South American camelids) with respiratory
beendetectedinSouthAmericancamelidsorinBactriancamels disease(Jinetal.,2007).AbetaCoV(bovineCoV-likeCoVwithno
(Chanetal.,2015;MackayandArden,2015).Itseemsthatinfec- genome sequenced) was isolated from NWCs and dromedaries
tionof dromedarieswithMERS-CoVislimitedtoAfricaandthe withdiarrhoea(Crossleyetal.,2010,2012).Transmissionof the
MiddleEast(Pereraetal.,2013;Reuskenetal.,2013;Cormanetal., betaCoVoccursdirectlythroughclosecontactandaerosols,and
2014a;Hemidaetal.,2014;Meyeretal.,2014;Mulleretal.,2014). theincubationperiodincriasisshort(24–48h).DiseaseinNWCs
Over90%ofalldromedariesinvestigatedfromthisregionpossess occurs in association with infection with rotavirus, E. coli, and
antibodiestothevirus,someofthematleastformorethan30years CryptosporidiumandSalmonellaspp.(Werneryetal.,2014).CoVs
(Mulleretal.,2014).MERS-CoVinfectionindromedariesisnota havebeenlinkedtoseveraloutbreaksofdiarrhoeaaffectingNWCs
newentityandonlyveryfewyounganimals(<1%)maydevelopnasal ofallagesonfarmsinnorthwestUSAandSouthAmerica.Sero-
dischargewithoutotherclinicalsigns.Thispicturechangeswhen logicalsurveysandvirusidentificationhavealsobeencarriedout.
dromedariesareexperimentallyinfectedthroughtheintranasalroute CoVswerealsodetectedindromedaryfaecalsamplesandantibod-
(Haagmansetal.,2016). ieshavebeendetectedindromedaryserainEastAfricaandonthe
Inhumanbeings,closecontactwiththeseyoungdromedaries ArabianPeninsula(Reuskenetal.,2013;Meyeretal.,2014;Muller
may result in MERS-CoV infection, sometimes with fatal conse- etal.,2014).However,therearenoreportsonCoVinBactriancamels
quences.Althoughthemodeofhuman-to-humantransmissionof (Chanetal.,2015).
MERS-CoVisnotfullyunderstood,thevirushascausedmajornoso- In2014,wediscoveredanovelCoVnameddromedarycamelCoV
comialoutbreaksathospitalsinSaudiArabia(Assirietal.,2013; UAE-HKU23(DcCoVUAE-HKU23);thecompletegenomeofthisvirus
Azharetal.,2014)andSouthKorea(Obohoetal.,2015).InSouth wassequenceddirectlyfromdromedaryfaecalsamplesanditsphy-
Korea,environmentalcontaminationhasbeendemonstrated,with logeneticrelationshipwithotherCoVswasdetermined(Table1)
MERS-CoVdetectedinpatients’rooms,medicaldevicesandairven- (Werneryetal.,2014).WespeculatethatthebovineCoV-likeCoV,
tilatingunits,leadingtoclosureofsomehospitals(Cowlingetal., withlimitedsequenceinformation,describedpreviously(Crossley
Table1
Coronavirusesfoundindromedaries.
Viruses Genera Hosts Geographicallocations
AlphaCoV Alphacoronavirus Alpacas,llamas,dromedaries USA,SaudiArabia
DcCoVUAEHKU23 Betacoronavirus(lineageA) Dromedaries UAE,SaudiArabia
MERS-CoV Betacoronavirus(lineageC) Humanbeings,dromedaries SaudiArabia,Yemen,Oman,UnitedArabEmirates,Egypt,Jordan,Iran,Turkey,
Greece,Italy,Germany,France,England,USA,Korea,China,Thailand,Malaysia
78 U.Werneryetal./TheVeterinaryJournal220(2017)75–79
etal.,2010,2012),isprobablyDcCoVUAE-HKU23.Phylogeneticanal- Conflictofintereststatement
ysisshowsthatCoVUAE-HKU23iscloselyrelatedtootherCoVsof
theBetacoronavirus1speciesinbetaCoVlineageA,ofwhichbovine Noneoftheauthorsofthispaperhasafinancialorpersonalre-
CoVandhumanCoVOC43aremembers(Wooetal.,2014d).Re- lationship with other people or organisations that could
cently,wesuccessfullyisolatedDcCoVUAE-HKU23usingthehuman inappropriatelyinfluenceorbiasthecontentofthepaper.
rectaltumourHRT-18Gcelllineandconfirmedthatitisdifferent
fromthebetaCoVinalpacasusingbioinformaticsapproaches(Woo
Acknowledgements
etal.,2016b).AlthoughbothMERS-CoVandDcCoVUAE-HKU23are
betaCoVs,thereisminimalcrossantigenicitybetweenthem,as
This work is partly supported by the Theme-based Research
shownbyvariousserologicaltests(Wooetal.,2014d).Lastyear,
Scheme(projectnumberT11/707/15),UniversityGrantsCommit-
anotheralphaCoVthathasbeenfoundinalpacaswasalsodiscov-
tee,HealthandMedicalResearchFund,UniversityDevelopment
ered in nasal samples of dromedaries (Table 1). The camelid
FundandStrategicResearchThemeFund,UniversityofHongKong.
alphaCoV,togetherwithMERS-CoVandDcCoVUAE-HKU23,were
We thank Emily Y. M. Wong for her assistance in preparing the
observedtobeco-circulatingincamelsinSaudiArabia(Sabiretal.,
manuscript.
2016).
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