Bat Coronaviruses in China


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Bat Coronaviruses in China

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Bat Coronaviruses in China
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Viruses
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Fan, Yi
Zhao, Kai
Shi, Zheng-Li
Zhou, Peng
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MDPI
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Coronavirus ( local )
Bat ( local )
Epidemiology ( local )
Cross-Species ( local )
Zoonosis ( local )
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serial ( sobekcm )

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During the past two decades, three zoonotic coronaviruses have been identified as the cause of large-scale disease outbreaks–Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and Swine Acute Diarrhea Syndrome (SADS). SARS and MERS emerged in 2003 and 2012, respectively, and caused a worldwide pandemic that claimed thousands of human lives, while SADS struck the swine industry in 2017. They have common characteristics, such as they are all highly pathogenic to humans or livestock, their agents originated from bats, and two of them originated in China. Thus, it is highly likely that future SARS- or MERS-like coronavirus outbreaks will originate from bats, and there is an increased probability that this will occur in China. Therefore, the investigation of bat coronaviruses becomes an urgent issue for the detection of early warning signs, which in turn minimizes the impact of such future outbreaks in China. The purpose of the review is to summarize the current knowledge on viral diversity, reservoir hosts, and the geographical distributions of bat coronaviruses in China, and eventually we aim to predict virus hotspots and their cross-species transmission potential.
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Viruses, Vol. 11, no. 3 (2019-03-02).

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Review BatCoronavirusesinChina YiFan 1,2 ,KaiZhao 1,2 ,Zheng-LiShi 1,2 andPengZhou 1,2, * 1CASKeyLaboratoryofSpecialPathogensandBiosafety,WuhanInstituteofVirology,ChineseAcademyofSciences,Wuhan430071,China;yifanfs0224@163.comY.F.;chiukal@163.comK.Z.; zlshi@wh.iov.cnZ.-L.S. 2 UniversityofChineseAcademyofSciences,Beijing100049,China * Correspondence:peng.zhou@wh.iov.cn Received:29January2019;Accepted:26February2019;Published:2March2019 Abstract:Duringthepasttwodecades,threezoonoticcoronaviruseshavebeenidentiedasthecauseoflarge-scalediseaseoutbreaks–SevereAcuteRespiratorySyndromeSARS,MiddleEastRespiratorySyndromeMERS,andSwineAcuteDiarrheaSyndromeSADS.SARSandMERSemergedin2003and2012,respectively,andcausedaworldwidepandemicthatclaimedthousandsofhumanlives,whileSADSstrucktheswineindustryin2017.Theyhavecommoncharacteristics,suchastheyareallhighlypathogenictohumansorlivestock,theiragentsoriginatedfrombats,andtwoofthemoriginatedinChina.Thus,itishighlylikelythatfutureSARS-orMERS-likecoronavirusoutbreakswilloriginatefrombats,andthereisanincreasedprobabilitythatthiswilloccurinChina.Therefore,theinvestigationofbatcoronavirusesbecomesanurgentissueforthedetectionofearlywarningsigns,whichinturnminimizestheimpactofsuchfutureoutbreaksinChina.Thepurposeofthereviewistosummarizethecurrentknowledgeonviraldiversity,reservoirhosts,andthegeographicaldistributionsofbatcoronavirusesinChina,andeventuallyweaimtopredictvirushotspotsandtheircross-speciestransmissionpotential. Keywords: coronavirus;bat;epidemiology;cross-species;zoonosis 1.IntroductionFifteenyearsafterthersthighlypathogenichumancoronaviruscausedthesevereacuterespiratorysyndromecoronavirusSARS-CoVoutbreak,anothersevereacutediarrheasyndromecoronavirusSADS-CoVdevastatedlivestockproductionbycausingfataldiseasesinpigs.BothoutbreaksbeganinChinaandwerecausedbycoronavirusesofbatorigin[1,2].ThisincreasedtheurgencytostudybatcoronavirusesinChinatounderstandtheirpotentialofcausinganothervirusoutbreak.Inthisreview,wecollectedinformationfrompastepidemiologystudiesonbatcoronavirusesinChina,includingthevirusspeciesidentied,theirhostspecies,andtheirgeographicaldistributions.Wealsodiscussthefutureprospectsofbatcoronavirusescross-speciestransmissionandspreadinChina. 2.WhyStudyBatCoronavirusesinChina? 2.1.CoronavirusTaxonomyCoronavirusesCoVsbelongtothesubfamilyOrthocoronavirinaeinthefamilyCoronaviridaeandtheorderNidovirales.CoVshaveanenveloped,crown-likeviralparticlefromwhichtheywerenamedafter.TheCoVgenomeisapositive-sense,single-strandRNA+ssRNA,27kbinsize,whichisthesecondlargestofallRNAvirusgenomes.Typically,twothirdsofthegenomicRNAencodesfortwolargeoverlappingpolyproteins,ORF1aandORF1b,thatareprocessedintotheviralViruses 2019 , 11 ,210;doi:10.3390/v11030210www.mdpi.com/journal/viruses

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Viruses 2019 , 11 ,210 2of14polymeraseRdRpandothernonstructuralproteinsinvolvedinRNAsynthesisorhostresponsemodulation.TheotherthirdofthegenomeencodesforfourstructuralproteinsspikeS,envelopeE,membraneM,andnucleocapsidNandotheraccessoryproteins.WhiletheORF1a/ORF1bandthefourstructuralproteinsarerelativelyconsistent,thelengthoftheCoVgenomeislargelydependentonthenumberandsizeofaccessoryproteins[3].ComparedwithotherRNAviruses,theexpandedgenomesizeofCoVsisbelievedtobeassociatedwithincreasedreplicationdelity,afteracquiringgenesencodingRNA-processingenzymes[4].GenomeexpansionfurtherfacilitatestheacquisitionofgenesencodingaccessoryproteinsthatarebenecialforCoVstoadapttoaspecichost[5].Asaresult,genomechangescausedbyrecombination,geneinterchange,andgeneinsertionordeletionarecommonamongCoVs.TheCoVsubfamilyisexpandingrapidly,duetotheapplicationofnextgenerationsequencingwhichhasincreasedthedetectionandidenticationofnewCoVspecies.Asaresult,CoVtaxonomyisconstantlychanging.AccordingtothelatestInternationalCommitteeofTaxonomyofVirusesICTVclassication,therearefourgenera-,-,-,and-consistingofthirty-eightuniquespeciesinthesubfamily[6].Thenumberofspecieswillcontinuetoincrease,astherearestillmanyunclassiedCoVs[7,8].CoVscausediseaseinavarietyofdomesticandwildanimalsaswellasinhumans,where-and-CoVsmainlyinfectmammalsand-and-CoVsmainlyinfectbirdsTable1.Twohighlypathogenic -CoVs,SARS-CoV,andMERS-CoVhavecausedpandemicsinhumanssince2002[1,9].OriginatinginChinaandthenspreadingtootherpartsoftheworld,SARS-CoVinfectedaround8000individualswithanoverallmortalityof10%duringthe2002pandemic[1].Sinceitsemergencein2012intheMiddleEast,MERS-CoVspreadto27countries,resultingin2249laboratory-conrmedcasesofinfectionwithanaveragemortalityof35.5%untilSeptember2018[9].Besidesthesetwoviruses,-CoVs229EandNL63and-CoVsOC43andHKU1canalsocauserespiratorydiseasesinhumans[10].Moreover,CoVscausepandemicdiseaseindomesticandwildanimalsTable1.SADS-CoVwasrecentlyidentiedastheetiologicalagentresponsibleforalarge-scaleoutbreakoffataldiseaseinpigsinChinathatcausedthedeathofmorethan20,000piglets[2].PorcineepidemicdiarrheavirusPEDVandtransmissiblegastroenteritisvirusTGEVthatbelongto-CoVandporcine-CoVPDCoVarealsoimportantemergingandre-emergingvirusesinpigsthatposesignicanteconomicthreattotheswineindustry[11].Inaddition,avianinfectiousbronchitisvirusIBV,-CoVcausesahighlycontagiousdiseasethataffectspoultryproductionworldwide[12].CoronaviruseshavealsobeenassociatedwithcatarrhalgastroenteritisinminkMCoVandwhaledeathsBWCoV-SW1[13,14].2.2.LinkingBatstoCoronavirusesBataretheonlymammalswiththecapabilityofpoweredight,whichenablesthemtohavealongerrangeofmigrationcomparedtolandmammals.Batsarealsothesecondlargestorderofmammals,accountingforaboutafthofallmammalianspecies,andaredistributedworldwide.Phylogeneticanalysisclassiedbatsintotwolargesuborders—theYinpterochiroptera,consistingofonePteropodidaemegabatandveRhinolophoideamicrobatfamilies,andtheYangochiropteracomprisingatotalofthirteenmicrobatfamilies[15].Itishypothesizedthatightprovidedtheselectionpressureforcoexistencewithviruses,whilethemigratoryabilityofbatshasparticularrelevanceinthecontextofdiseasetransmission[16].Indeed,batswerelinkedtoafewhighlypathogenichumandiseases,supportingthishypothesis.Someofthesewellcharacterizedbatviruses,includingbatlyssavirusesRabiesvirus,henipavirusesNipahvirusandHendravirus,CoVsSARS-CoV,MERS-CoV,andSADS-CoV,andlovirusesMarburgvirus,Ebolavirus,andMenglavirus,poseagreatthreattohumanhealth[16,17].Acomprehensiveanalysisofmammalianhost–virusrelationshipsdemonstratedthatbatsharborasignicantlyhigherproportionofzoonoticvirusesthanothermammalianorders[18].Virusesfrommostoftheviralfamiliescanbefoundinbats[16].BatsarenowrecognizedasimportantreservoirhostsofCoVsTable1.AlthoughcivetcatswereinitiallyidentiedastheanimaloriginofSARS-CoV,batsweresoonfoundtobethemostlikelynatural

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Viruses 2019 , 11 ,210 3of14reservoirhostsofthisvirus[19–21].Long-termsurveillancerevealedanaverage10%SARS-relatedCoVnucleotidepositivityinbats,includingsomevirusesthatcanusesamehumanentryreceptorACE2asSARS-CoV[7,22].Similarly,batshavebeenproposedtoharbortheprogenitorvirusesofMERS-CoV,althoughdromedarycamelscantransmitthisvirustohumansdirectly[9].ThemostrecentSADS-CoVspilloverwastracedbacktobats[2].Inaddition,batsalsocarry-CoVsthatarerelatedtopathogenichuman229E-andNL63-CoVs,aswellaspandemicswinecoronavirusPEDV[23,24].Insummary,batscarrymajor-outof17and-outof12CoVspeciesthatmayspillovertohumansandcausediseaseTable1.Attributedtothewidedistributionofbats,CoVscanbefoundworldwide,includingChina[25]. 2.3.WhyChina?TwobatCoVscausedoutbreaksinChina;itisthusurgenttostudythereasonstoavoidfutureoutbreaks.Chinaisthethirdlargestterritoryandisalsothemostpopulousnationintheworld.Avasthomelandplusdiverseclimatesbringaboutgreatbiodiversityincludingthatofbatsandbat-borneviruses—mostoftheICTVcoronavirusspecies/38werenamedbyChinesescientistsstudyinglocalbatsorothermammals.ThemajorityoftheCoVscanbefoundinChinaTable1.Moreover,mostofthebathostsoftheseCoVslivenearhumans,potentiallytransmittingvirusestohumansandlivestock.Chinesefoodculturemaintainsthatliveslaughteredanimalsaremorenutritious,andthisbeliefmayenhanceviraltransmission.Itisgenerallybelievedthatbat-borneCoVswillre-emergetocausethenextdiseaseoutbreak.Inthisregard,Chinaisalikelyhotspot.Thechallengeistopredictwhenandwhere,sothatwecantryourbesttopreventsuchoutbreaks.

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Viruses 2019 , 11 ,210 4of14 Table1. InternationalCommitteeofTaxonomyofVirusesICTVclassicationofcoronavirusesspecies,reservoirhosts,andpresencereportedinChina. CoronavirusSpeciesAbbreviationsHumanBatsOtherAnimalsReportedinChina BatcoronavirusHKU10BtCoV-HKU10YesYes[7,8,26,27] -CoV BatcoronavirusCDPHE15BtCoV-CDPHE15YesNo Rhinolophusferrumequinum alphacoronavirusHuB-2013BtRfCoV-HuB13YesYes[8] *Humancoronavirus229EHCoV-229EYesYes[28,29] LuchengRnratcoronavirusLRNVYesratYes[30] FerretcoronavirusFRCoVYesferretNo[31] *Minkcoronavirus1MCoVYesminkNo[14] Miniopterus batcoronavirus1BtMiCoV-1YesYes[7,8,32–37] Miniopterus batcoronavirusHKU8BtMiCoV-HKU8YesYes[7,8,33–35,37–41] Myotisricketti alphacoronavirusSax-2011BtMy-Sax11YesYes[8,37] Nyctalusvelutinus alphacoronavirusSC-2013BtNy-Sc13YesYes[8] *PorcineepidemicdiarrheavirusPEDVYespigYes[42] Scotophilus batcoronavirus512BtScCoV-512YesYes[37] * Rhinolophus batcoronavirusHKU2SADS BtRhCoV-HKU2YesYesYes[2,7,8,38,43–45] *HumancoronavirusNL63HCoV-NL63YesYes[28,29] NL63-relatedbatcoronavirusstrainBtKYNL63-9bBtKYNL63YesNo[24] *Alphacoronavirus1TransmissiblegastroenteritisvirusTGEVYespigYes[42] China Rattus coronavirusHKU24RtCoV-HKU24YesratYes[46] -CoV *HumancoronavirusHKU1HCoV-HKU1YesYes[28,29] *MurinecoronavirusMurinehepatitiscoronavirusMHVYesmouseNo[47] Bat Hp -betacoronavirusZhejiang2013BtHpCoV-ZJ13YesYes[8] Hedgehogcoronavirus1EriCoV-1YeshedgehogNo[48] *MiddleEastrespiratorysyndrome-relatedcoronavirus MERSr-CoVYesYesYes[49,50] Pipistrellus batcoronavirusHKU5BtPiCoV-HKU5YesYes[38,39,49,51,52] Tylonycteris batcoronavirusHKU4BtTyCoV-HKU4YesYes[36,38,39,49–51] Rousettus batcoronavirusGCCDC1 # BtEoCoV-GCCDC1 YesYes[53–55] Rousettus batcoronavirusHKU9BtRoCoV-HKU9YesYes[39,55–57] *Severeacuterespiratorysyndrome-relatedcoronavirus SARSr-CoVYesYesYes[7,8,20–22,27,37,40,45,58–64] *Betacoronavirus1HumancoronavirusOC43HCoV-OC43YesYes[28,29] WigeoncoronavirusHKU20WiCoV-HKU20YesbirdYes[65] -CoV BulbulcoronavirusHKU11BuCoV-HKU11YesbirdYes[65] CoronavirusHKU15PoCoV-HKU15YespigYes[66] MuniacoronavirusHKU13MuCoV-HKU13YesbirdYes[65] White-eyecoronavirusHKU16WECoV-HKU13YesbirdYes[65] NightheroncoronavirusHKU19NHCoV-HKU19YesbirdYes[65] CommonmoorhencoronavirusHKU21CMCoV-HKU21YesbirdYes[65] * ? BelugawhalecoronavirusSW1 BWCoV-SW1YeswhaleNo[13] -CoV *AvianinfectiousbronchitisvirusIBVYesbirdYes[12] *Thedisease-causingCoVsareindicatedandthethreezoonoticCoVsareinbold.*?BWCoV-SW1wasfoundinasickwhale,butwhetheritwastheetiologicalagentoftheinfectionwasnotproven.#Carrierofthisviruswasconrmedas Eonycterisspelaea ,butnot Rousettus bats.Theviruswasrenamedaccordingly.

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Viruses 2019 , 11 ,210 5of14 3.BatCoronavirusesThatAreAssociatedwithDiseases 3.1.SARS-RelatedCoronavirusesInNovember2012,therstcaseofSARSwasrecordedinFoshancity,GuangdongProvince,ChinaFigure1.In2005,twoindependentChinesegroupsreportedtherstbatSARS-relatedCoVSARSr-CoVthatwascloselyrelatedtohumanSARS-CoV,implyingabatoriginofthelatter[20,21].Sincethen,morebatSARSr-CoVisolateswereidentiedinChinaTable1.GenomeidentitiesofthesebatSARSr-CoVsareashighas92%tohumanSARS-CoV,buttheirmajorreceptorbindingspikeproteinscannotusethehumanvirusentryreceptorACE2[67].WhethertheyaretheprogenitorvirusesofSARS-CoVisdebatable.In2013,theisolationofabatSARSr-CoVthatusestheACE2receptorprovidedthestrongestevidenceofthebatoriginofSARS-CoV[22].Furthermore,thebuildingblocksforSARS-CoVwereidentiedfromelevendifferentSARSr-CoVviralstrainsinave-yearsurveillanceprograminacaveinhabitedbymultiplespeciesofhorseshoebatsinYunnanProvince,China[62]. Figure1.GeographicaldistributionofbatcoronavirusesCoVsandtheircorrespondingbathostsinChina.EachredboxrepresentsoneCoVpositivesamplefoundinthatparticularbatspecies.OnedotmatrixwasdrawnforeachprovincewhereaCoVpositivesamplehadbeenreported.GuangdongProvince,whereSARSandSADSbegan,iscircledinred.Abbreviationsofbatspeciesandvirusspeciesareindicated. SARSr-CoVsfoundinChinashowgreatgenomicdiversityFigure2.Sequenceidentitiesoftheconserved440bpRdRpregionrangesfrom80to100%withhumanSARS-CoV.CoVdiversityinbatsisthoughttobeshapedbybothspeciesrichnessandgeographicaldistribution,andCoVsexhibitclusteringatthebatgeneralevel,withthesegenus-specicclusterslargelyassociatedwithdistinctCoVspecies[25].Ouranalysissupportsthistheory.SARSr-CoVsarepresentindifferentbatspeciesbutallbelongtothefamilyofRhinolophidaeandHipposideridaeFigure1.Chaerephonplicatabatswerealsoreportedascarriersinonestudy,butthiscannotbeconclusivelysupportedwithoutmolecularidenticationofthebatspecies[8].InChina,horseshoebatspeciesRhinolophusspp.arewidely

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Viruses 2019 , 11 ,210 6of14distributed,includingR.sinicus,R.ferrumequinum,R.macrotis,R.pearsoni,andR.pusillus,andarealsothemostfrequentSARSr-CoVcarriersthroughoutthenation[7,8,20–22,27,40,43,45,58,59,61–63,68]Figure1.ThemostvariableregionsamongbatSARSr-CoVsaretheSandORF8genes[62].TheSproteinincertainstrainsiscapableofusinghumanACE2asareceptorandthusposesadirectthreattohumans[69].Interestingly,alltheSARSr-CoVsthatarecapableofusinghumanACE2werefoundinR.sinicusinYunnanProvince[7,22,27,62].OtherSARSr-CoVsthatcannotusehumanACE2weredistributedinmultipleprovinces,fromnorthJilin,Shaanxi,ShanxitosouthHubei,Zhejiang,Yunnan,Guizhou,andGuangdongFigure1.Anotherprotein,ORF8,wassuggestedtobeimportantforinterspeciestransmission,asmosthumanSARS-CoVepidemicstrainscontainasignature29-nucleotidedeletioninORF8comparedtocivetSARSr-CoVs,whichresultsintheformationoftwoseparateopenreadingframes,ORF8aand8b[40].OnlytwoR.ferrumequinumandoneR.sinicusfromYunnanProvincecarriedvirusesthatpossessORF8proteinswithexceptionallyhighaminoacididentitiestothatofhuman/civetSARSr-CoVs[40,62].ItwasstronglysuggestedthatSARS-CoVmostlikelyoriginatedfromYunnan Rhinolophus batsviarecombinationeventsamongexistingSARSr-CoVs. Figure2.GeneticdiversityofbatCoVinChina.Sequencesof440bpconservedtheviralpolymeraseRdRpregionforeachCoVspecieswerecomparedtorelatedreferencesequences.Referencegenomesused:BtCoV-HKU10,NC_018871.1;BtRfCoV-HuB13,NC_028814.1;BtMiCoV-1,EU420138.1;BtMiCoV-HKU8,NC_010438.1;BtRhCoV-HKU2,MF094682.1;BtHpCoV-ZJ13,NC_025217.1;MERSr-CoV,NC_038294.1;BtPiCoV-HKU5,NC_009020.1;BtTyCoV-HKU4,NC_009019.1;BtRoCoV-GCCDC1,MG762606.1;BtRoCoV-HKU9,NC_009021.1;andSARSr-CoV,NC_004718.3.Notably,samplesthatwerepositiveforBtMy-Sax11,BtNy-Sc13,andBtScCoV-512werealsoidentiedinChina.Thesewerenottakenintoaccounthereastoofewsequenceswereavailable.ThesestudiesrevealedthatvariousSARSr-CoVscapableofusinghumanACE2arestillcirculatingamongbatsinChina,highlightingthepossiblyofanotherSARS-likediseaseoutbreak.CertainareasinYunnanProvincearehotspotsforspillover.Tosupportthishypothesis,weprovideserologicalevidenceofbatSARSr-CoVinfectioninhumansinYunnanProvincewherenopriorexposuretoSARS-CoVwasrecorded[70].ThemajorityoftheSARSr-CoVsappearnotabletouseACE2,buttheirinfectivityorpathogenesistohumansarestillunknown.FrequentinterspeciesrecombinationmayresultinanotherhumaninfectiouscoronavirusfromtheseSARSr-CoVs.Furthermore,therearestillunansweredquestionsaboutSARS,e.g.,`WhydidtherstSARScaseoccurinGuangdongProvince,butallthehuman-ACE2-usingSARSr-CoVswerefoundinYunnanProvince?'and'WhydoesR.sinicusincertainareascarryhuman-ACE2-usingSARSr-CoVsbutnootherRhinolophusspeciescarrythesameviruses?'Aboveall,furtherextensivesurveillanceofSARSr-CoVsinChinaiswarranted.

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Viruses 2019 , 11 ,210 7of14 3.2.MERS-ClusterCoronavirusesDifferenttobatSARSr-CoV,MERS-clusterCoVswerefoundinbatsbeforetheMERSdiseaseoutbreaks.TwobatCoVs,TylonycterisHKU4andPipistrellusHKU5wererstdescribedasputativegroup2cCoVsin2006inChina.TheywereassociatedwiththeHCoV-EMCMERS-CoVthatstartedthe2012pandemic[9,38,39].ItisgenerallyacceptedthatMiddleEastdromedarycamelswerethemajoranimalsourceforthezoonotictransmissionofhumanMERS,whilebatsharborCoVsthatsharedcommonancestrywithMERS-CoV[71].ExtensiveglobalsurveysrevealedawidedistributionoflargelydivergedMERS-clusterCoVslineage2cCoVs[71].TwocloselyrelatedNeoromiciazuluensisbatCoVs,NeoCoVandPREDICT/PDF-2180,weresubsequentlyfound,furthersupportingtheideathatMERS-CoVwasdescendedfromanancestralvirusofAfricanbats[72,73].Sofar,threespeciesoflineage2cCoVshavebeenfoundinbats,accordingtothelatestCoVtaxonomyreports.BasedonphylogenetictreesconstructedusingRdRp,ORF1,S1,andNsequences,batMERS-relatedCoVsMERSr-CoVsaretheclosestrelativesofMERS-CoV,followedbyHKU4-CoVandHKU5-CoV.However,intheS1region,MERS-CoVwasmuchclosertoHKU4-CoVthantoMERSr-CoVorHKU5-CoV.Likewise,pseudovirusassaysshowedthattheMERSr-CoVHKU25and422CoVspikeproteincanusehumanDPP4forentryintohDPP4-expressingcells,althoughwithlowerefciencythanthatofMERS-CoVorHKU4-CoVspikeproteins[49,50].ThereisnoevidenceofHKU5-CoVusingthehumanDPP4receptor[74].AllthreetypesofbatMERS-clusterCoVscanbefoundinChinaFigures1and2.TheirreservoirhostsallbelongtotheVespertilionidaefamily.MERSr-CoVcanbefoundinmultiplebatspecies,includingPipistrellusbatsP.abramusandP.pipistrellus,greateveningbatsIaio,particoloredbatsVespertiliosuperans,andChinesepipistrellebatsHypsugopulveratus[49,50,52].Duetothiswidehostspectrum,MERSr-CoValsoshowedalargegeneticdiversity,rangingfrom72to100%intheconserved440bpRdRpregion.Incontrast,HKU4-CoVswereonlycarriedbyTylonycterisbatsT.pachypusandT.robustulaandwererelativelyconserved[38,39,49]Figure2.HKU5-CoVswerefoundindifferentPipistrellusbatsP.abramus,P.pipistrellus,P.minus,andP.spp.[8,36,38,39,49,51].LikeHKU4-CoVs,theyarealsorelativelyconserved.Therangeofdistributionvaries,dependingonMERS-clusterCoVspecies.HKU5-CoVsshouldbethemostwidelydistributedCoVsamongthethreeastheirhosts,Pipistrellusbats,liveclosetohumans.However,thereportedCoVpositivesamplescanonlybefoundinGuangdong,HongKong,andMacau,possiblyduetoalackofinvestigationinotherprovinces.Incontrast,MERSr-CoVswerereportedinmultiplebatspeciesinSichuan,Guangdong,andHongKongatamuchlowerlevelthanHKU5-CoVs.Similarly,Tylonycterisbatsareararebatspeciesthatliveinbamboo,whichrestrictedthedistributionofHKU4-CoVstocertainlocationsinGuangdong,Guangxi,Yunnan,Guizhou,HongKong,andMacauFigure1.Tosumup,itappearsthattheriskofMERS-clusterCoVspillovertohumansleadingtoanepidemicinChinaislowforthefollowingreasons:thegeographicaldistributionofMERSr-CoVsandHKU4-CoVsthathavethepotentialtoinfecthumanscapableofusinghumanentryreceptorsislimited,andHKU5-CoVsthatwidelyexistinChinesebatsacrossthenationhavenotobtainedtheabilityofusinghumanentryreceptors.However,weshouldnotunderestimatethepossibilityofrecombinationamongdifferentbatCoVsthatleadtothegenerationofpotentialpandemicviruses. 3.3.HKU2SADS-RelatedCoVHKU2r-CoVHKU2r-CoVshaveonlybeenreportedinChinaandKenya.FromstudiesinChina,HKU2r-CoVshavebeenfrequentlyfoundinRhinolophusbatsR.afnis,R.sinicus,R.rex,andR.pusillusinseveralprovincesbeforetheSADSoutbreak[2,7,8,38,41,44].Sofar,thevirushasbeenreportedinHongKong,Guangdong,Yunnan,andTibet.ThereareperhapsmoretobediscoveredinotherprovincesconsideringthewiderangeofRhinolophusbats.Notably,thesebatspecies,whichconstantlyinteractwithbothlivestockandhumansinChina,alsoharborSARSr-CoVsseeSection3.1.Likewise,HKU2r-CoVsshowedahighgeneticdiversitywithSARSr-CoVsFigure2.Duetothesecharacteristics,HKU2r-CoVswerelistedasvirusesthatwerehighlylikelytocrossspeciestohumans.Thenovel

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Viruses 2019 , 11 ,210 8of14HKU2r-CoV,swineacutediarrheasyndromecoronavirusSADS-CoV,wasidentiedastheetiologicalagentresponsibleforalarge-scaleoutbreakoffataldiseaseinpigsinChina,GuangdongProvincein2017[2].TheentryreceptorofSADS-CoVhasnotbeenidentied,yetthisvirusshowedacapacityforinfectingawiderangeofhuman,swine,andbatcellsunpublisheddata.InChina,thehighdensityofpigfarmsandthewidedistributionofhostbatspeciespromotethepossibilityoffutureHKU2r-CoVcross-speciestransmission[75].Thus,studiesonbatHKU2r-CoVsspilloverpotentialandtheirpathogenesisareurgent. 4.ASADS-CoVModelofPredictionandOtherHotspotVirusesTopredictthenextCoVthatwillcauseavirusoutbreakinfuture,welistthegeneralfactorsthatmaycontributetothisoutbreak.Firstly,batshostalargenumberofhighlydiverseCoVs.ItisknownthatCoVgenomesregularlyundergorecombinationduringinfection,andarichgenepoolcanfacilitatethisprocess.Secondly,batspeciesarewidelydistributedandliveclosetohumans.Thirdly,thevirusesarepathogenicandtransmissible.Inthiscontext,SADS-CoVandSARS-CoVoutbreaksinChinaarenotunexpected.Bythismodel,thereareotherCoVsthathavenotyetcausedvirusoutbreaksbutshouldbemonitored.WithinthefamilyVespertilionidae,themouse-earedbatsMyotiswhichfavorroostinginabandonedhumanfacilitiesarealsoawidespreadgenusofbatsbesidesPipistrellusbats.TheycarryalargenumberandgeneticallydiversiedHKU6-CoVsthatarecloselyrelatedtoMyotisricketti-CoVSax-2011[36,38].Moreover,bent-wingedbatsMiniopterusspp.carryalargevarietyof-CoVs.OneofthemostfrequentlydetectedvirusesisHKU8-CoV,whichwasrstdescribedcirculatinginM.pusillusinHongKongin2005.Later,itwasalsofoundinM.magnate,M.fuliginosus,andM.schreibersiiinHongKong,Guangdong,Yunnan,Fujian,andHubeiprovinces,showingagreatgeneticdiversity[32–35,37,41,60]Figure1.BesidesHKU8-CoVs,bent-wingedbatsMiniopterusspp.alsoharboralargeamountofMiniopterusbatCoV1BtMiCoV-1,whichwerecalledCoV1AorCoV1Bpreviously.ThisviralspecieswasfoundalmostasfrequentlyasHKU8-CoVinmultipleprovincesinChinainMiniopterusbats,althoughthesevirusesshowedarelativelysmallsequencevariationbetweeneachother[32–35,37,41,60].GeneticanalysisindicatesthatBtMiCoV-1,HKU8-CoV,andHKU7-CoVpreviousnamearedifferentbutcloselyrelatedCoVscirculatinginbent-wingedbatsandmayhavedescendedfromacommonancestor[34].Additionally,RousettusleschenaultiibatsinthefamilyofPteropodidaeharborHKU9-CoVs.Asafruitbat,RousettusleschenaultiihasawideryingrangethanmostoftheinsectivorousbatsinChina,thusitmaycarryvirusesoverlongdistances.AcomparisonofthereportedHKU9-CoVsequencesshowedahighgeneticdiversitywithinthisviralspecies[55–57]Figure2.ThelastCoVthatshouldbementionedisHKU10-CoV.HKU10-CoVscanbefoundinbatsfromdifferentgeneraRousettusleschenaultiiandHipposiderospomona,suggestinginterspeciestransmissionbetweenbats[7,26,27,39].AgeneticdifferencecanalsobeobservedforthisvirusspeciesFigure2.Aboveall,thesevirusestwellinourSADSpredictionmodelandshouldbemonitoredinourfuturestudies. 5.OtherBatCoVsinChinaIn2016,anovel-CoV,Ro-BatCoVGCCDC1,wasidentiedfromtheRousettusleschenaultiibat.However,weconrmedthehostwasacloselyrelatedEonycterisspelaeabatuponspeciesidenticationandthenrenamedthevirusasBtEoCoV-GCCDC1Table1.Theuniquenessofthisvirusisthatitcontainsagenethatmostlikelyoriginatedfromthep10geneofabatorthoreovirus[53].Atwo-yearfollow-upstudyalsoillustratedthatBtEoCoV-GCCDC1persistentlycirculatesamongbats.DifferenttothegeneticallydivergedHKU9-CoV,thisvirusishighlyconservedFigure2.BtEoCoV-GCCDC1hasonlybeenfoundinsouthYunnanProvincesofar[54,55].Inaddition,thereareotherbatCoVsthathavebeenidentiedinChina:Rhinolophusferrumequinum-CoVHuB-2013[8],Myotisricketti-CoVSax-2011[8,37],Nyctalusvelutinus-CoVSC-2013[8],ScotophilusbatCoV512[37],Hipposiderosbat-CoVZhejiang2013,andaMurinaleucogasterbatCoV,whichhasbeendescribedastheevolutionary

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Viruses 2019 , 11 ,210 9of14ancestorofPEDV[37].Notably,therearestillmanyunclassiedbatCoVscirculatinginChina,particularlyinthenorthernpartofthenationwherebatviruseswererarelystudiedFigure1.AccordingtothecriteriadenedbytheICTV,theCoVfamilywillmostlikelyexpandfollowingfurtherinvestigationofbatCoVsinChina. 6.CoexistenceofDifferentCoronavirusesorOtherVirusesinBatsThecoexistenceofmorethantwovirusesinthesamebatisquitecommonforsomebatspecies.ThecoexistenceofMiniopterusbatCoV1andHKU8-CoVinonebathasbeenfrequentlyreported[7,34].AnotherexampleisthecoexistencebetweenRhinolophusHKU2-CoVsSADS-CoVandSARSr-CoVsthatcausedthevirusoutbreaks,respectively[2,45].Real-timemonitoringthisbatgenusisnecessaryforthepreventionoffutureSARS-likeoutbreaks.Moreover,twoormoredistinctgenotypesofHKU9-CoVswerereportedtocoexistinasingleRousettusbat[56].ThecoexistenceofHKU9-CoVsandanewidentiedbatlovirusMenglavirusthatisphylogeneticallyrelatedtotheEbolaandMarburgviruseswasalsoidentiedfromRousettusbats[17,55].Giventhatabatorthoreovirusp10genewasincorporatedintheBtEoCoV-GCCDC1genome,recombinationbetweenthebatlovirusandHKU9-CoVcannotbeexcluded.Otherpairswerealsorecorded—HKU8-CoVwithunclassied-CoV[7],HKU2-CoVwithunclassied-CoV[7],HKU10-CoVwithunclassied-CoV[7],andHKU6-CoVwithbatadenovirus[36]. 7.ConclusionsTwobatoriginCoVscausedlarge-scaleepidemicsinChinaoverfourteenyears,highlightingtheriskofafuturebatCoVoutbreakinthisnation.Inthisreview,wehavesummarizedthecurrentndingsrelatedtobatCoVepidemiologyinChina,aimingtoexploretheassociationsbetweenCoVspecies,batspecies,andgeographicallocations,andeventuallyweaimtopredictthecross-speciestransmissionpotentialofthesebatCoVs.Admittedly,theanalysismaybeaffectedbyinaccurateorincompletedata.Forexample,notallresearchgroupsperformedbatspeciesidenticationorusedGlobalPositioningSystemGPSduringbatsampling.Batsinthenorthorwestprovinceswerenotsurveyedeither.Nonetheless,webelievethisanalysisisagoodstartingpointforfurtherresearch.Moreover,thereareotheroutstandingquestionsthatshouldbeaddressedinfuturestudies:giventhatmostoftheICTVclassiedCoVspeciesarefrombats,whytherearesomanygeneticallydivergentCoVsinbats,thepathogenesisofmostbatCoVsinhumansremainsunknownastheviruseshaveneverbeenisolatedorrescued—apartfromthevirusesidentiedduringtheoutbreaks,manyvirusesposeathreattohumanhealth,althoughSARS-CoVandSADS-CoVwereknowntobetransmittedfrombatstohumanorswine,theirexacttransmissionroutesareunknown,andwhybatscanmaintainCoVslong-termwithoutshowingclinicalsymptomsofdiseases.Auniquebatimmunitymodelhasbeenproposed.Theauthorshaveshownthatconstitutivelyexpressedbatinterferonmayprotectbatsfrominfection[76],whilesomeparticularlydampenedimmunepathwaysmayallowbatstohaveahighertoleranceagainstviraldiseases[77].Whilewestarttounveilthemysteryofuniquebatimmunity,thereisstilllongwaytogobeforewecanfullyunderstandtherelationshipbetweenbatsandcoronaviruses. AuthorContributions:P.Z.andZ.-L.S.designedthestudy.Y.F.andK.Z.analyzedthedata.P.Z.andY.F.preparedthemanuscript. Funding:TheworkwassupportedbyChina'sNationalScienceandTechnologyMajorProjectonInfectiousDiseasesZX10101004andtheNationalNaturalScienceFoundationofChinaExcellentYoungScholarstoPZ81822028and81661148058. ConictsofInterest: Theauthorsdeclarenoconictofinterest.

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