Emerging coronaviruses: Genome structure, replication, and

The genome of CoVs is a single-stranded positive-sense RNA (+ssRNA) (~30 kb) with 5′-cap structure and 3′-poly-A tail. The genomic RNA is used ... SkiptoArticleContent SkiptoArticleInformation JournalofMedicalVirologyVolume92,Issue4p.418-423 REVIEWFreeAccess Emergingcoronaviruses:Genomestructure,replication,andpathogenesis Correction(s)forthisarticle Emergingcoronaviruses:Genomestructure,replication,andpathogenesis YuChen, QianyunLiu, DeyinGuo, Volume92Issue10JournalofMedicalVirology pages:2249-2249 FirstPublishedonline:August2,2020 YuChen, CorrespondingAuthor [email protected] StateKeyLaboratoryofVirology,ModernVirologyResearchCenter,CollegeofLifeSciences,WuhanUniversity,Wuhan,China CorrespondenceYuChen,ModernVirologyResearchCenter,CollegeofLifeSciences,WuhanUniversity,Wuhan430072,China. Email:[email protected] DeyinGuo,CenterforInfectionandImmunityStudy,SchoolofMedicine,SunYat-senUniversity,Guangzhou510080,China. Email:guodeyin@mail.sysu.edu.cnSearchformorepapersbythisauthorQianyunLiu, StateKeyLaboratoryofVirology,ModernVirologyResearchCenter,CollegeofLifeSciences,WuhanUniversity,Wuhan,ChinaSearchformorepapersbythisauthorDeyinGuo, CorrespondingAuthor [email protected] orcid.org/0000-0002-8297-0814 CenterforInfectionandImmunityStudy,SchoolofMedicine,SunYat-senUniversity,Guangzhou,China CorrespondenceYuChen,ModernVirologyResearchCenter,CollegeofLifeSciences,WuhanUniversity,Wuhan430072,China. Email:[email protected] DeyinGuo,CenterforInfectionandImmunityStudy,SchoolofMedicine,SunYat-senUniversity,Guangzhou510080,China. Email:[email protected] YuChen, CorrespondingAuthor [email protected] StateKeyLaboratoryofVirology,ModernVirologyResearchCenter,CollegeofLifeSciences,WuhanUniversity,Wuhan,China CorrespondenceYuChen,ModernVirologyResearchCenter,CollegeofLifeSciences,WuhanUniversity,Wuhan430072,China. Email:[email protected] DeyinGuo,CenterforInfectionandImmunityStudy,SchoolofMedicine,SunYat-senUniversity,Guangzhou510080,China. Email:guodeyin@mail.sysu.edu.cnSearchformorepapersbythisauthorQianyunLiu, StateKeyLaboratoryofVirology,ModernVirologyResearchCenter,CollegeofLifeSciences,WuhanUniversity,Wuhan,ChinaSearchformorepapersbythisauthorDeyinGuo, CorrespondingAuthor [email protected] orcid.org/0000-0002-8297-0814 CenterforInfectionandImmunityStudy,SchoolofMedicine,SunYat-senUniversity,Guangzhou,China CorrespondenceYuChen,ModernVirologyResearchCenter,CollegeofLifeSciences,WuhanUniversity,Wuhan430072,China. Email:[email protected] DeyinGuo,CenterforInfectionandImmunityStudy,SchoolofMedicine,SunYat-senUniversity,Guangzhou510080,China. Email:[email protected] Firstpublished:22January2020 https://doi.org/10.1002/jmv.25681Citations:1,270AboutSectionsPDF ToolsRequestpermissionExportcitationAddtofavoritesTrackcitation ShareShare GiveaccessSharefulltextaccessSharefull-textaccessPleasereviewourTermsandConditionsofUseandcheckboxbelowtosharefull-textversionofarticle.IhavereadandaccepttheWileyOnlineLibraryTermsandConditionsofUseShareableLinkUsethelinkbelowtoshareafull-textversionofthisarticlewithyourfriendsandcolleagues.Learnmore.CopyURL SharealinkShareonEmailFacebookTwitterLinkedInRedditWechat Abstract Therecentemergenceofanovelcoronavirus(2019-nCoV),whichiscausinganoutbreakofunusualviralpneumoniainpatientsinWuhan,acentralcityinChina,isanotherwarningoftheriskofCoVsposedtopublichealth.Inthisminireview,weprovideabriefintroductionofthegeneralfeaturesofCoVsanddescribediseasescausedbydifferentCoVsinhumansandanimals.ThisreviewwillhelpunderstandthebiologyandpotentialriskofCoVsthatexistinrichnessinwildlifesuchasbats. Highlights Thegeneralfeaturesofcoronavirusesareintroduced. Theriskofemergingcoronavirusesincludingthe2019-nCoVisdescribed. Thegenomestructureandreplicationmechanismofcoronavirusesareprovided. Thediseasescausedbythemajorcoronavirusesarelisted. 1INTRODUCTION Coronaviruses(CoVs)areimportantpathogensforhumanandvertebrates.Theycaninfectrespiratory,gastrointestinal,hepatic,andcentralnervoussystemofhuman,livestock,birds,bat,mouse,andmanyotherwildanimals.1-3Theoutbreaksofthesevereacuterespiratorysyndrome(SARS)in2002/2003andtheMiddleEastrespiratorysyndrome(MERS)in2012havedemonstratedthepossibilityofanimal-to-humanandhuman-to-humantransmissionofnewlyemergingCoVs.4,5AnoutbreakofmysterypneumoniainWuhansinceDecember2019hasbeendrawingtremendousattentionaroundtheworld.Chinesegovernmentandresearchershavebeentakingswiftmeasurestocontroltheoutbreakandconducttheetiologicalstudies.Thecausativeagentofthemysterypneumoniahasbeenidentifiedasanovelcoronavirus(nCoV)bydeepsequencingandetiologicalinvestigationsbyatleastfiveindependentlaboratoriesofChina(http://virological.org/andhttps://www.gisaid.org/).On12January2020,theWorldHealthOrganizationtemporarilynamedthenewvirusas2019novelcoronavirus(2019-nCoV).ThesporadicemergenceandoutbreaksofnewtypesofCoVsremindusthatCoVsareasevereglobalhealththreat.ItishighlylikelythatnewCoVoutbreaksareunavoidableinthefutureduetochangesoftheclimateandecology,andtheincreasedinteractionsofhumanwithanimals.Thus,thereisanurgentneedtodevelopeffectivetherapiesandvaccinesagainstCoVs. 2CORONAVIRALGENOMESTRUCTUREANDREPLICATION CoVsbelongtothesubfamilyCoronavirinaeinthefamilyofCoronaviridaeoftheorderNidovirales,andthissubfamilyincludesfourgenera:Alphacoronavirus,Betacoronavirus,Gammacoronavirus,andDeltacoronavirus(Figure 1A).ThegenomeofCoVsisasingle-strandedpositive-senseRNA(+ssRNA)(~30 kb)with5′-capstructureand3′-poly-Atail.ThegenomicRNAisusedastemplatetodirectlytranslatepolyprotein1a/1ab(pp1a/pp1ab),whichencodesnonstructuralproteins(nsps)toformthereplication-transcriptioncomplex(RTC)inadouble-membranevesicles(DMVs).6Subsequently,anestedsetofsubgenomicRNAs(sgRNAs)aresynthesizedbyRTCinamannerofdiscontinuoustranscription.7ThesesubgenomicmessengerRNAs(mRNAs)possesscommon5′-leaderand3′-terminalsequences.TranscriptionterminationandsubsequentacquisitionofaleaderRNAoccursattranscriptionregulatorysequences,locatedbetweenopenreadingframes(ORFs).Theseminus-strandsgRNAsserveasthetemplatesfortheproductionofsubgenomicmRNAs.8,9 Figure1OpeninfigureviewerPowerPoint Thegenomicstructureandphylogenetictreeofcoronaviruses.A,ThephylogenetictreeofrepresentativeCoVs,withthenewcoronavirus2019-nCoVhighlightedinred.B,Thegenomestructureoffourgeneraofcoronaviruses.Pp1aandpp1brepresentthetwolongpolypeptidesthatareprocessedinto16nonstructuralproteins.S,E,M,andNindicatethefourstructuralproteinsspike,envelope,membrane,andnucleocapsid.2019-nCoV,2019novelcoronavirus;CoVs,coronavirus;HE,hemagglutinin-esterase.Viralnames:HKU,coronavirusesidentifiedbyHongKongUniversity;HCoV,humancoronavirus;IBV,infectiousbronchitisvirus;MHV,murinehepatitisvirus;TGEV,transmissiblegastroenteritisvirus ThegenomeandsubgenomesofatypicalCoVcontainatleastsixORFs.ThefirstORFs(ORF1a/b),abouttwo-thirdsofthewholegenomelength,encode16nsps(nsp1-16),exceptGammacoronavirusthatlacksnsp1.Thereisa−1frameshiftbetweenORF1aandORF1b,leadingtoproductionoftwopolypeptides:pp1aandpp1ab.Thesepolypeptidesareprocessedbyvirallyencodedchymotrypsin-likeprotease(3CLpro)ormainprotease(Mpro)andoneortwopapain-likeproteaseinto16nsps.10,11OtherORFsontheone-thirdofthegenomenearthe3′-terminusencodesatleastfourmainstructuralproteins:spike(S),membrane(M),envelope(E),andnucleocapsid(N)proteins.Besidesthesefourmainstructuralproteins,differentCoVsencodespecialstructuralandaccessoryproteins,suchasHEprotein,3a/bprotein,and4a/bprotein(Figure 1B,lowerpanel).AllthestructuralandaccessoryproteinsaretranslatedfromthesgRNAsofCoVs.7 ThegenomesequencealignmentofCoVsshows58%identityonthensp-codingregionand43%identityonthestructuralprotein-codingregionamongdifferentCoVs,with54%atthewholegenomelevel(Figure 1B,upperpanel),suggestingthenspsaremoreconservedandthestructuralproteinsaremorediverseinneedofadaptationtonewhosts.SincethemutationratesinthereplicationofRNAvirusesaremuchhigherthanthatofDNAviruses,thegenomesofRNAvirusesareusuallylessthan10 kbinlength.However,theCoVgenomeismuchlarger,withroughly30 kbinlength,thelargestknownRNAviruses.ThemaintenanceofsuchalargegenomeofCoVsmayberelatedtothespecialfeaturesoftheCoVRTC,whichcontainsseveralRNAprocessingenzymessuchasthe3′-5′exoribonucleaseofnsp14.The3′-5′exoribonucleaseisuniquetoCoVsamongallRNAviruses,probablyprovidingaproofreadingfunctionoftheRTC.12-14Sequenceanalysisshowsthatthe2019-nCoVpossessesatypicalgenomestructureofCoVandbelongstotheclusterofbetacoronavirusesthatincludesBat-SARS-like(SL)-ZC45,Bat-SLZXC21,SARS-CoV,andMERS-CoV.BasedonthephylogenetictreeofCoVs,2019-nCoVismorecloselyrelatedtobat-SL-CoVZC45andbat-SL-CoVZXC21andmoredistantlyrelatedtoSARS-CoV(Figure 1A). 3FUNCTIONSOFNONSTRUCTURALANDSTRUCTURALPROTEINSINCORONAVIRALREPLICATION Mostofthenspsofnsp1-16havebeenreportedfortheirspecificrolesinthereplicationofCoVs.However,thefunctionsofsomeofthenspsareunknownornotwellunderstood.Theknownfunctionsofthe16nspsaresummarizedinTable 1. nsps Functions References nsp1 CellularmRNAdegradation,inhibitingIFNsignaling 15,16 nsp2 Unknown 17,18 nsp3 PLP,polypeptidescleaving,blockinghostinnateimmuneresponse,promotingcytokineexpression 19,20 nsp4 DMVformation 21,22 nsp5 3CLpro,Mpro,polypeptidescleaving,inhibitingIFNsignaling 23-25 nsp6 Restrictingautophagosomeexpansion,DMVformation 26,27 nsp7 Cofactorwithnsp8andnsp12 28,29 nsp8 Cofactorwithnsp7andnsp12,primase 28-30 nsp9 DimerizationandRNAbinding 31,32 nsp10 Scaffoldproteinfornsp14andnsp16 33-36 nsp11 Unknown 37 nsp12 PrimerdependentRdRp 28,38,39 nsp13 RNAhelicase,5′triphosphatase 40-42 nsp14 Exoribonuclease,N7-MTase 12,43-45 nsp15 Endoribonuclease,evasionofdsRNAsensors 46-48 nsp16 2′-O-MTase;avoidingMDA5recognition,negativelyregulatinginnateimmunity 34,35,49 Abbreviations:3CLpro,chymotrypsin-likeprotease;DMV,double-membranevesicle;dsRNA,double-strandedRNAviruses;IFN,interferon;mRNA,messengerRNA;Mpro,mainprotease. FourstructuralproteinsareessentialforvirionassemblyandinfectionofCoVs.HomotrimersofSproteinsmakeupthespikesontheviralsurfaceandtheyareresponsibleforattachmenttohostreceptors.50,51TheMproteinhasthreetransmembranedomainsanditshapesthevirions,promotesmembranecurvature,andbindstothenucleocapsid.52,53TheEproteinplaysaroleinvirusassemblyandrelease,anditinvolvedinviralpathogenesis.54,55TheNproteincontainstwodomains,bothofwhichcanbindvirusRNAgenomeviadifferentmechanisms.ItisreportedthatNproteincanbindtonsp3proteintohelptetherthegenometoRTC,andpackagetheencapsidatedgenomeintovirions.56-58Nisalsoanantagonistofinterferon(IFN)andviralencodedrepressorofRNAinterference,whichappearstobebeneficialfortheviralreplication.59 3.1DiversityofCoVpathogenesis DifferentCoVsdisplaydiversehostrangeandtissuetropism.Usually, alphacoronavirusesandbetacoronavirusesinfectmammals.Incontrast,gammacoronavirusesanddeltacoronavirusesinfectbirdsandfish,butsomeofthemcanalsoinfectmammals.4,60Before2019,therewereonlysixCoVsthatwereknowntoinfecthumanandcauserespiratorydiseases.HCoV-229E,HCoV-OC43,HCoV-NL63,andHKU1causeonlymildupperrespiratorydisease,andinrarecasessomeofthemcancausesevereinfectionininfants,youngchildrenandelders.SARS-CoVandMERS-CoVcaninfectlowerrespiratorytractandcausesevererespiratorysyndromeinhuman.56,61SomeCoVscaninfectlivestock,birds,bats,mice,whales,andmanyotherwildanimals,andtheycancausegreateconomicloss.Forexample,in2016,anHKU2-relatedbatCoV,swineacutediarrheasyndromeCoV,causedalarge-scaleoutbreakoffataldiseaseinpigsinSouthernChina,andmorethan24 000pigletsweredead.62ThisisthefirstdocumentedspilloverofabatCoVthatcausedseverediseaseinlivestock.4,63 ThenewCoV,2019-nCoV,whichbelongstobetacoronavirusesbasedonsequenceanalysis(Figure 1A),canalsoinfectthelowerrespiratorytractandcausepneumoniainhuman,butitseemsthatthesymptomsaremilderthanSARSandMERS.Upto20January2020,291casesintotalhavebeenconfirmedinChinabysequenceanalysis,clinicaldiagnosisandepidemiologicalexamination,including270casesinWuhanand21casesinBeijing,Shanghai,andGuangdong(http://www.nhc.gov.cn/yjb/new_index.shtml).Inaddition,fourcaseswereconfirmedinthreeothercountries,includingtwocasesinThailand,onecaseinJapan,andonecaseinSouthKorea;allthesepatientshadstayedinorvisitedWuhan2weeksbeforetheonsetofthesymptoms.Sixdeathsand63patientswithseveresymptomswerereportedinWuhan(http://wjw.wuhan.gov.cn/).Amongthesixdeathcases,fourpatientswithpublishedinformationareelderpeopleofover60yearsoldandhaveotherillnessesbeforetheinfection,suchasabdominaltumorandchronicliverdisease,myocarditisandrenaldysfunction,andcardiovasculardisease. ManyofthepatientshavedirectorindirectcontactwiththeWuhanHuananSeafoodWholesaleMarketthatisbelievedtobetheoriginalplaceoftheoutbreakofthe2019-nCoV.However,transmissionof2019-nCoVfromfishtohumanisunlikely.The2019-nCoVandfishCoVssuchasBelugaWhaleCoV/SW1belongtodifferentgeneraandapparentlyhavedifferenthostranges.AstheWuhanseafoodmarketalsosellsotheranimals,thenaturalhostof2019-nCoVawaitstobeidentified.Duetothepossibilityoftransmissionfromanimaltohuman,CoVsinlivestockandotheranimalsincludingbatsandwildanimalssoldinthemarketshouldbeconstantlymonitored.Inaddition,moreandmoreevidenceindicatethenewvirus2019-nCoVisspreadviatherouteofhuman-to-humantransmissionbecausethereareinfectionsofpeoplewhodidnotvisitWuhanbuthadclosecontactwithfamilymemberswhohadvisitedWuhanandgotinfected(http://www.cctv.com/). ThemajorpathogenicCoVsarelistedinTable 2forbetterunderstandingthepathogenesisofCoVs. Virus Genus Host Symptoms HumanCoV-229E Alpha Human Mildrespiratorytractinfections HumanCoV-NL63 Alpha Human Mildrespiratorytractinfections PRCV/ISU-1 Alpha Pig Mildrespiratorytractinfections TGEV/PUR46-MAD Alpha Pig Diarrhea,with100%mortalityinpigletslessthan2-wk-old PEDV/ZJU-G1-2013 Alpha Pig Severewaterydiarrhea SeACoV-CH/GD-01 Alpha Pig Severeandacutediarrheaandacutevomiting CanineCoV/TU336/F/2008 Alpha Dog Mildclinicalsigns,diarrhea Camelalphacoronavirusisolatecamel/Riyadh Alpha Camel Asymptomatic Felineinfectiousperitonitisvirus Alpha Cat Fever,vasculitis,andserositis,withorwithouteffusions HumanCoV-HKU1 Beta Human Pneumonia HumanCoV-OC43 Beta Human Mildrespiratorytractinfections SARS-CoV Beta Human Severeacuterespiratorysyndrome,10%mortalityrate MERS-CoV Beta Human Severeacuterespiratorysyndrome,37%mortalityrate BovineCoV/ENT Beta Cow Diarrhea EquineCoV/Obihiro12-1 Beta Horse Fever,anorexia,leucopenia MHV-A59 Beta Mouse Centralnervoussystemdiseaseandhepatitis BelugaWhaleCoV/SW1 Gamma Whale Pulmonarydisease,terminalacuteliverfailure IBV Gamma Chicken Severerespiratorydisease BulbulcoronavirusHKU11 Delta Bulbul Respiratorydisease(collectedfromrespiratorytractofdeadwildbirds) SparrowcoronavirusHKU17 Delta Sparrow Respiratorydisease(collectedfromrespiratorytractofdeadwildbirds) 4TREATMENTANDPREVENTION Atpresent,thereisnosinglespecificantiviraltherapyforCoVandthemaintreatmentsaresupportive.RecombinantIFNwithribavirinonlyhaslimitedeffectsagainstCoVsinfection.64AfterSARSandMERSepidemics,greateffortshavebeendevotedtodevelopmentofnewantiviralstargetingCoVsproteases,polymerases,MTases,andentryproteins,however,noneofthemhasbeenshowntobeefficaciousinclinicaltrials.65-67Plasmaandantibodiesobtainedfromtheconvalescentpatientshavebeenproposedforuseintreatment.68 Inaddition,variousvaccinestrategies,suchasusinginactivatedviruses,live-attenuatedviruses,viralvector-basedvaccines,subunitvaccines,recombinantproteins,andDNAvaccines,havebeendevelopedbuthaveonlybeenevaluatedinanimalssofar.69,70 Sincethereisnoeffectivetherapyorvaccine,thebestmeasuresnowaretocontrolthesourceofinfection,earlydiagnosis,reporting,isolation,supportivetreatments,andtimelypublishingepidemicinformationtoavoidunnecessarypanic.Forindividuals,goodpersonalhygiene,fittedmask,ventilation,andavoidingcrowdedplaceswillhelptopreventCoVsinfection. 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CrossrefPubMedWebofScience®GoogleScholar CitingLiterature Volume92,Issue4SpecialIssue:2019NovelCoronavirusOrigin,Evolution,Disease,BiologyandEpidemiology:Part‐IApril2020Pages418-423 Thisarticlealsoappearsin:Newcoronavirus2019-nCoVandtheoutbreakoftherespiratoryillness FiguresReferencesRelatedInformation CloseFigureViewerReturntoFigurePreviousFigureNextFigureCaption DownloadPDF Thefulltextofthisarticlehostedatiucr.orgisunavailableduetotechnicaldifficulties. LogintoWileyOnlineLibrary EmailorCustomerID Password Forgotpassword? NEWUSER> INSTITUTIONALLOGIN> ChangePassword OldPassword NewPassword TooShort Weak Medium Strong VeryStrong TooLong PasswordChangedSuccessfully Yourpasswordhasbeenchanged Createanewaccount EmailorCustomerID Returninguser Forgotyourpassword? Enteryouremailaddressbelow. EmailorCustomerID Pleasecheckyouremailforinstructionsonresettingyourpassword. 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