Human Coronavirus EMC Is Not the Same as Severe Acute Respiratory Syndrome Coronavirus.

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by  Perlman, Stanley

COMMENTARY
Human Coronavirus EMC Is Not the Same as Severe Acute
Respiratory Syndrome Coronavirus
StanleyPerlman,JincunZhao
DepartmentofMicrobiology,UniversityofIowa,IowaCity,Iowa,USA
ABSTRACT Anewlyidentifiedbetacoronavirus,humancoronavirusEMC(HCoV-EMC),hasbeenisolatedfromseveralpatients
withrespiratoryandrenaldiseaseintheMiddleEast.Whileonlyafewinfectedpatientshavebeenidentified,themortalityofthe
infectionisgreaterthan50%.Likeitsbetter-knowncousinsevereacuterespiratorysyndromecoronavirus(SARS-CoV),HCoV-
EMCappearstohaveoriginatedfrombats.InarecentarticleinmBio,Mülleretal.describedseveralimportantdifferencesbe-
tweenthetwoviruses[M.A.Mülleretal.,mBio3(6):e00515-12,2012,doi:10.1128/mBio.00515-12].UnlikeSARS-CoV,HCoV-
EMCcandirectlyinfectbatcells.Asimportant,HCoV-EMCdoesnotentercellsusingtheSARS-CoVreceptor,human
angiotensin-convertingreceptor-2(hACE2).Theseresultsprovideastrongincentiveforidentifyingthehostcellreceptorused
byHCoV-EMC.Identificationofthereceptorwillprovideinsightintothepathogenesisofpulmonaryandrenaldiseaseandmay
alsosuggestnoveltherapeuticinterventions.
Therecentidentificationofanovelhumancoronavirus,EMC sequently,thesevirusesareabletoinfectmosttissueculturecells
(HCoV-EMC),asthecausativeagentforseverehumanrespi- andalsotospreadtoinfectalargevarietyofruminants(4).
ratorydiseaseraisedfearsthataversionofthe2002-2003severe Second, uncommon human transmissibility may also reflect
acuterespiratorysyndrome(SARS)epidemicwouldrecur.This usageofaproteinthatispresentpredominantlyinthelowerre-
fear prompted intense research efforts that resulted in publica- spiratorytractsofhumans.EventhoughSARS-CoVcausedare-
tionsdescribingtheclinicalcharacteristicsofthehumaninfection spiratory disease with high morbidity and mortality, it was not
andcompletesequenceandgenomiccharacterizationofthevirus easilytransmissiblebetweenhumans,inpartbecauseitsreceptor,
(1).Additionalanalysesshowedthatthattheviruswasrelatedto hACE2, is most abundant in the lungs and less so in the upper
twopreviouslyidentifiedbatcoronaviruses.Preliminarysequence airway(5).Consequently,mostSARS-CoV-infectedpatientswere
analysisofvirusisolatedfromaPipistrelluspipistrellusbatinthe notcontagiousuntilaftertheydevelopedpneumonia,withspread
Netherlandssuggestedanevencloserrelationship,with88%nu- occurringvialargedroplets.Thisresultedinahighproportionof
cleotideidentitytoafragmentoftheRNA-dependentRNApoly- secondary cases being close contacts (either family members or
merase.InarecentarticleinmBio,Mülleretal.providedimpor- healthcareworkers)andalsoenabledtheeffectivenessofquaran-
tantinformationaboutthehostcellreceptorusedbythevirusto tiningincontrollingtheinfection.Parenthetically,afewindivid-
infectcells(2).First,thereceptorisnothumanACE2(hACE2), ualswereabletospreadSARS-CoVveryefficiently(superspread-
whichisusedbytheSARScoronavirustoinfecthumans.Second, ingevents)(6),andtheseeventshadadisproportionateeffecton
thevirusisabletoinfecthuman,bat,andporcinecells.Thelatter thewidespreadnatureoftheinfection.Virusburdenswerepre-
resultisremarkable,becausecoronavirusesingeneralshowfairly sumed to be higher in patients associated with superspreading
stricthostspecificity;inearlystudiesofanotherbetacoronavirus, events, with enhanced spread via fine droplets. Whether these
mousehepatitisvirus,serialpassagewasrequiredforadaptation eventsreflecteddifferencesinlocalizationofhACE2throughout
tohumancells(3). theairway,ininnatecell,Tcell,orantibodyresponses,orinex-
WeknownowthathACE2isnottheHCoV-EMCreceptor,but pression of another factor was not determined before the epi-
clearly, identification of the host cell receptor used by HCoV- demicwascontrolled.
EMCisahighpriority.Thelimitedinformationthatisavailable IfthereceptorforHCoV-EMCisaprotein,itispredictedto
suggests several possibilities about the identity of the receptor. haveadistributionsimilartothatofACE2oranevenmorepro-
First, human transmission may occur but is not common. This nouncedlocalizationtothelowerrespiratorytract,givenitsap-
disparitybetweensevereinfectionandpoortransmissibilityalso parentlackofhuman-to-humanspread.Itwillalsobeinteresting
occursinpatientsinfectedwiththeinfluenzaAvirusH5N1strain to determine whether the receptor is an ectopeptidase. Several
(IAV-H5N1). IAV-H5N1 enters cells via glycans that contain a alphacoronaviruses, including HCoV-229E and transmissible
terminal(cid:1)2,3-linkedsialicacid,unlikehumanstrainsofthevirus, gastroenteritisvirus,apathogenicporcinecoronavirus,useami-
whichbindtoterminal(cid:1)2,6-linkedsialicacidmoieties.Terminal nopeptidaseN(APN).BothAPNandhACE2areectopeptidases
(cid:1)2,3-linked sialic acid proteins are not common in the human
airwayandarelargelyrestrictedtothelowerairway,explaining Published15January2013
thepoortransmissibilityexhibitedbythevirus.Useofaglycanfor CitationPerlmanS,ZhaoJ.2013.HumancoronavirusEMCisnotthesameassevere
cell entry, either as a primary or binding ligand, might allow acuterespiratorysyndromecoronavirus.mBio4(1):e00002-13.doi:10.1128/mBio.00002-
13.
HCoV-EMCtoinfectcellsfromavarietyofspeciesand,depend-
Copyright©2013PerlmanandZhaoThisisanopen-accessarticledistributedunder
ingonthelocationinthelungofthespecificglycaninquestion,
thetermsoftheCreativeCommonsAttribution-Noncommercial-ShareAlike3.0
mayexplainthelackoftransmissibilitybetweenhumans.Thereis
Unportedlicense,whichpermitsunrestrictednoncommercialuse,distribution,and
precedentforsialicacidusagebycoronaviruses:bothbovinecoro- reproductioninanymedium,providedtheoriginalauthorandsourcearecredited.
navirusandHCoV-OC43entercellsviabindingsialicacid.Con- AddresscorrespondencetoStanleyPerlman,[email protected].
January/February2013 Volume4 Issue1 e00002-13 ® mbio.asm.org 1
Commentary
andcleaveN-terminalaminoacidsfromsmallpeptides.However, resultinclinicaldisease.This,inturn,mayresultinnovelthera-
inneitherinstanceistheenzymaticactivityoftheproteinrequired peuticinterventionstodiminishimmunopathologicaldisease.
forreceptorfunction,suggestingthatthestructureoftheectodo- Whileidentificationofthereceptorwillbeanimportantad-
mainofeachmoleculeisespeciallyamenabletocoronavirusbind- vance,theoverarchingquestionatpresentiswhetherHCoV-EMC
ing.InadditiontoservingasthereceptorforSARS-CoV,ACE2 isorwillbecomeanimportanthumanpathogen.Atthispoint,
haslung-protectiveproperties.DownregulationofACE2,asoc- fewerthan10caseshavebeenidentifiedandthemortalityratehas
curs during SARS-CoV infection, is believed to contribute to beengreaterthan50%.Withsofewcases,infectionandanalysisof
pathologicalchangesinthelung(7).Itwillbeofinteresttodeter- laboratoryanimalswillberequiredtofulfillKoch’spostulatesand
mineifthereceptorforHCoV-EMChassimilarproperties. prove a causative role for HCoV-EMC in respiratory disease. If
Identificationofthereceptormayalsoshedlightonapoten- HCoV-EMCisassociatedwithrespiratorydiseaseinanimals,as
tially novel aspect of HCoV-EMC pathogenesis. Initial reports seemslikely,epidemiologicalstudiestoprovideadenominatorfor
thetotalnumberofcaseswillbeessential.IsHCoV-EMCacom-
suggestthatrenalfailureispartofthediseaseprocess(8),although
moninfectionintheMiddleEast,withmostpatientsremaining
atthispointitisimpossibletoknowwhetherthisisaspecificeffect
asymptomaticordevelopingmilddisease,oristheinfectionrare,
or a consequence of the multiorgan failure that often occurs in
butwheninfectionoccurs,diseaseissevere?Developmentoftools
severelyillpatients.Ifkidneyinvolvementisdocumentedinmost
todetectpastandpresentinfectionsiscriticalandwillbefacili-
patients,identificationoftheHCoV-EMCreceptormayprovidea
tated by recent publications of the virus sequence and genomic
basisforunderstandingwhyrenaldiseaseiscommon.TheSARS-
analysis.Equallyimportantwillbethecollectionandanalysisof
CoVreceptor,ACE2,ispresentathighlevelsinthehumankidney,
samplesfromrepresentativepopulationsintheMiddleEast.Most
andSARS-CoVwasdetectedinthekidneysofsomepatientsdur-
patientsinfectedwithSARS-CoVdevelopedclinicaldisease,with
ingthe2002-2003epidemic,butrenaldiseasedidnotoccurcom-
onlyafewinfectionsremainingasymptomatic.IfHCoV-EMCisa
monly during the infection (5). Understanding the differential
newpathogen,willitfurtheradapttohumanpopulations,asthe
abilitiesofHCoV-EMCandSARS-CoVtocauserenaldiseasewill
SARS-CoVdidduringthe2002-2003epidemic(4,6)?Ifvirusis
provideinsightintoauniqueaspectoftheHCoV-EMCinfection.
detectedonlyrarelyinhumanpopulationsandneverspreadssig-
Ofnote,coronavirusinfectionoftherespiratorytractandrenal
nificantlyfromhumantohuman,itmaynotbeamajorhealth
systemhasbeendescribedinchickensinfectedwithanothercoro-
issue,buttheinterestingquestionofhowtheseunluckyindividu-
navirus,infectiousbronchitisvirus(IBV)(9).IBVisbestknownas
alswereinfectedremainstobeaddressed.
animportantcausativeagentforupperrespiratorytractdiseasein
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2 ® mbio.asm.org January/February2013 Volume4 Issue1 e00002-13