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MERS-CoV Edited by Fang Li and Lanying Du Printed Edition of the Special Issue Published in Viruses www.mdpi.com/journal/viruses MERS-CoV MERS-CoV SpecialIssueEditors FangLi LanyingDu MDPI•Basel•Beijing•Wuhan•Barcelona•Belgrade Special Issue Editors Fang Li LanyingDu Department of Veterinary ViralImmunologyLaboratory, and Biomedical Sciences, LindsleyF.KimballResearchInstitute, University of Minnesota NewYorkBloodCenter USA USA EditorialOffice MDPI St.Alban-Anlage66 4052Basel,Switzerland ThisisareprintofarticlesfromtheSpecialIssuepublishedonlineintheopenaccessjournalViruses (ISSN1999-4915)from2018to2019(availableat: https://www.mdpi.com/journal/viruses/special issues/MERSCoV). Forcitationpurposes,citeeacharticleindependentlyasindicatedonthearticlepageonlineandas indicatedbelow: LastName,A.A.; LastName,B.B.; LastName,C.C.ArticleTitle. JournalNameYear,ArticleNumber, PageRange. ISBN978-3-03921-850-9(Pbk) ISBN978-3-03921-851-6(PDF) (cid:2)c 2019bytheauthors. ArticlesinthisbookareOpenAccessanddistributedundertheCreative Commons Attribution (CC BY) license, which allows users to download, copy and build upon publishedarticles,aslongastheauthorandpublisherareproperlycredited,whichensuresmaximum disseminationandawiderimpactofourpublications. ThebookasawholeisdistributedbyMDPIunderthetermsandconditionsoftheCreativeCommons licenseCCBY-NC-ND. Contents AbouttheSpecialIssueEditors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii FangLiandLanyingDu MERSCoronavirus:AnEmergingZoonoticVirus Reprintedfrom:Viruses2019,11,663,doi:10.3390/v11070663 . . . . . . . . . . . . . . . . . . . . . 1 ElmoubasherFarag,ReinaS.Sikkema,TinkaVinks,MdMazharulIslam,MohamedNour, Hamad Al-Romaihi, Mohammed Al Thani, Muzzamil Atta, Farhoud H. Alhajri, Salih Al-Marri,MohdAlHajri,ChantalReuskenandMarionKoopmans DriversofMERS-CoVEmergenceinQatar Reprintedfrom:Viruses2019,11,22,doi:10.3390/v11010022 . . . . . . . . . . . . . . . . . . . . . 7 ZhiqiSong,YanfengXu,LinlinBao,LingZhang,PinYu,YajinQu,HuaZhu,WenjieZhao, YunlinHanandChuanQin FromSARStoMERS,ThrustingCoronavirusesintotheSpotlight Reprintedfrom:Viruses2019,11,59,doi:10.3390/v11010059 . . . . . . . . . . . . . . . . . . . . . 22 W.Widagdo,SyriamSooksawasdiNaAyudhya,GadissaB.HundieandBartL.Haagmans HostDeterminantsofMERS-CoVTransmissionandPathogenesis Reprintedfrom:Viruses2019,11,280,doi:10.3390/v11030280 . . . . . . . . . . . . . . . . . . . . . 50 Bingpeng Yan, Hin Chu, Dong Yang, Kong-Hung Sze, Pok-Man Lai, Shuofeng Yuan, HuipingShuai, YixinWang, RichardYi-TsunKao, JasperFuk-WooChanandKwok-Yung Yuen CharacterizationoftheLipidomicProfileofHumanCoronavirus-InfectedCells: Implications forLipidMetabolismRemodelinguponCoronavirusReplication Reprintedfrom:Viruses2019,11,73,doi:10.3390/v11010073 . . . . . . . . . . . . . . . . . . . . . 64 W. Widagdo, Nisreen M.A. Okba, Mathilde Richard, Dennis de Meulder, Theo M. Bestebroer, Pascal Lexmond, Elmoubasher A.B.A. Farag, Mohammed Al-Hajri, Koert J. Stittelaar, Leon de Waal, Geert van Amerongen, Judith M.A. van den Brand, Bart L. HaagmansandSanderHerfst LackofMiddleEastRespiratorySyndromeCoronavirusTransmissioninRabbits Reprintedfrom:Viruses2019,11,381,doi:10.3390/v11040381 . . . . . . . . . . . . . . . . . . . . . 80 ChangfaFan,XiWu,QiangLiu,QianqianLi,SusuLiu,JianjunLu,YanweiYang,YuanCao, WeijinHuang,ChunnanLiang,TianleiYing,ShiboJiangandYouchunWang A Human DPP4-Knockin Mouse’s Susceptibility to Infection by Authentic and PseudotypedMERS-CoV Reprintedfrom:Viruses2018,10,448,doi:10.3390/v10090448 . . . . . . . . . . . . . . . . . . . . . 93 YusenZhou,YangYang,JingweiHuang,ShiboJiangandLanyingDu AdvancesinMERS-CoVVaccinesandTherapeuticsBasedontheReceptor-BindingDomain Reprintedfrom:Viruses2019,11,60,doi:10.3390/v11010060 . . . . . . . . . . . . . . . . . . . . . 113 CraigSchindewolfandVineetD.Menachery MiddleEastRespiratorySyndromeVaccineCandidates:CautiousOptimism Reprintedfrom:Viruses2019,11,74,doi:10.3390/v11010074 . . . . . . . . . . . . . . . . . . . . . 131 v Danielle R. Adney, Lingshu Wang, Neeltje van Doremalen, Wei Shi, Yi Zhang, Wing-Pui Kong,MeganR.Miller,TrentonBushmaker,DanaScott,EmmiedeWit,KayvonModjarrad, NikolaiPetrovsky,BarneyS.Graham,RichardA.BowenandVincentJ.Munster Efficacy of an Adjuvanted Middle East Respiratory Syndrome Coronavirus Spike Protein VaccineinDromedaryCamelsandAlpacas Reprintedfrom:Viruses2019,11,212,doi:10.3390/v11030212 . . . . . . . . . . . . . . . . . . . . . 148 SvenjaVeit,SylviaJany,RobertFux,GerdSutterandAsisaVolz CD8+TCellsRespondingtotheMiddleEastRespiratorySyndromeCoronavirusNucleocapsid ProteinDeliveredbyVacciniaVirusMVAinMice Reprintedfrom:Viruses2018,10,718,doi:10.3390/v10120718 . . . . . . . . . . . . . . . . . . . . . 161 LeiHe,WanboTai,JiangfanLi,YuehongChen,YaningGao,JunfengLi,ShihuiSun,Yusen Zhou,LanyingDuandGuangyuZhao Enhanced Ability of Oligomeric Nanobodies Targeting MERS Coronavirus Receptor-BindingDomain Reprintedfrom:Viruses2019,11,166,doi:10.3390/v11020166 . . . . . . . . . . . . . . . . . . . . . 179 Hui-JuHan,Jian-WeiLiu,HaoYuandXue-JieYu Neutralizing Monoclonal Antibodies as Promising Therapeutics against Middle East RespiratorySyndromeCoronavirusInfection Reprintedfrom:Viruses2018,10,680,doi:10.3390/v10120680 . . . . . . . . . . . . . . . . . . . . . 193 ShuaiXia,QiaoshuaiLan,JingPu,CongWang,ZezhongLiu,WeiXu,QianWang,HuanLiu, ShiboJiangandLuLu PotentMERS-CoVFusionInhibitoryPeptidesIdentifiedfromHR2DomaininSpikeProteinof BatCoronavirusHKU4 Reprintedfrom:Viruses2019,11,56,doi:10.3390/v11010056 . . . . . . . . . . . . . . . . . . . . . 203 CongWang,ChenHua,ShuaiXia,WeihuaLi,LuLuandShiboJiang CombiningaFusionInhibitoryPeptideTargetingtheMERS-CoVS2ProteinHR1Domainand aNeutralizingAntibodySpecificfortheS1ProteinReceptor-BindingDomain(RBD)Showed PotentSynergismagainstPseudotypedMERS-CoVwithorwithoutMutationsinRBD Reprintedfrom:Viruses2019,11,31,doi:10.3390/v11010031 . . . . . . . . . . . . . . . . . . . . . 215 YutingJiang,JunfengLi,YueTeng,HongSun,GuangTian,LeiHe,PeiLi,YuehongChen, YanGuo,JiangfanLi,GuangyuZhao,YusenZhouandShihuiSun Complement Receptor C5aR1 Inhibition Reduces Pyroptosis in hDPP4-Transgenic Mice InfectedwithMERS-CoV Reprintedfrom:Viruses2019,11,39,doi:10.3390/v11010039 . . . . . . . . . . . . . . . . . . . . . 227 RuiyingLiang,LiliWang,NaruZhang,XiaoqianDeng,MengSu,YudanSu,LanfangHu, ChenHe,TianleiYing,ShiboJiangandFeiYu DevelopmentofSmall-MoleculeMERS-CoVInhibitors Reprintedfrom:Viruses2018,10,721,doi:10.3390/v10120721 . . . . . . . . . . . . . . . . . . . . . 240 vi About the Special Issue Editors FangLiisanAssociateProfessorintheDepartmentofVeterinaryandBiomedicalSciencesatthe UniversityofMinnesota. Hismainlineofresearchexaminestheinvasionmechanismsofviruses. Specifically,hisgroupinvestigatesthestructuresandfunctionsofvirus-surfaceproteinsthatmediate receptor recognition and cell entry of viruses. His other line of research explores the structural and molecular basis for cancer and abnormal blood pressure. Specifically, his group investigates the structures and functions of mammalian-cell-surface enzymes that are critical for tumor cell growthandbloodpressureregulation. Basedonthesestructuralandfunctionalstudies,hisgroup furtherdevelopsnoveltherapystrategiestotreathumandiseases. HisresearchtoolsincludeX-ray crystallography,cryo-electronmicroscopy,proteinbiochemistry,molecularvirology,andvaccineand drugdesigns. Lanying Du is an Associate Member and Head of Viral Immunology Laboratory at Lindsley F. Kimball Research Institute of New York Blood Center, USA. Her research focuses are to: (1) design and develop effective and safe vaccines and therapeutic agents against coronaviruses (including MERS-CoV, SARS-CoV, and other coronaviruses with pandemic potential), influenza viruses, and flaviviruses (including the Zika virus and dengue virus); (2) understand protective mechanismsofthedevelopedvaccinesandtherapeutics; and(3)studypathogenicmechanismsof theseviruses,basedonwhichtodesignnovelvaccinesandtherapeutics. Herresearchtoolsinclude structure-based design of novel vaccines and therapeutics, mRNA technology, drug screening, andantibodyproductionandevaluation. vii viruses Editorial MERS Coronavirus: An Emerging Zoonotic Virus FangLi1,*andLanyingDu2,* 1 DepartmentofVeterinaryandBiomedicalSciences,CollegeofVeterinaryMedicine,UniversityofMinnesota, SaintPaul,MN55108,USA 2 LindsleyF.KimballResearchInstitute,NewYorkBloodCenter,NewYork,NY10065,USA * Correspondence:[email protected](F.L.);[email protected](L.D.); Tel.:+1-612-625-6149(F.L.);+1-212-570-3459(L.D.) Received:16July2019;Accepted:17July2019;Published:19July2019 Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging virus that was firstreportedinhumansinJune2012[1]. Todate, MERS-CoVcontinuestoinfecthumanswith a fatality rate of ~35%. At least 27 countries have reported human infections with MERS-CoV (https://www.who.int/emergencies/mers-cov/en/).MERS-CoVisazoonoticvirus.Likesevereacute respiratory syndrome coronavirus (SARS-CoV), MERS-CoV is believed to have originated from bats[2,3]. However,whereasthebat-to-humantransmissionofSARS-CoVwaslikelymediatedby palmcivetsasintermediatehosts,humanslikelyacquiredMERS-CoVfromdromedarycamels[4–6]. Human-to-humantransmissionofMERS-CoVdoesoccur, butitislimitedmostlytohealthcare environments [7,8]. Moreover, whereas SARS-CoV recognizes angiotensin-converting enzyme 2 (ACE2)asacellularreceptor[9,10],MERS-CoVusesdipeptidylpeptidase4(DPP4)toentertarget cells[11,12].Currently,novaccinesorantiviraltherapeuticshavebeenapprovedfortheprevention ortreatmentofMERS-CoVinfection,althoughanumberofthemhavebeendevelopedpreclinically and/ortestedclinically[13–16]. ThearticlesinthisspecialissueofViruseswerewrittenbyresearchersworkingintheMERS-CoV field.Themainaimsofthisissueareto(i)betterunderstandMERS-CoVtransmission,epidemiology,and pathogenesis;(ii)summarizecurrentprogressonMERS-CoVanimalmodels,vaccines,andtherapeutics; and(iii)discussfutureprospectsforMERS-CoVresearch.Thisissueincludessevenreviewarticles andnineoriginalresearchpapers,eachprovidingdetailedupdatesoncurrentMERS-CoVstudies. Studiesonthetransmission,epidemiology,andpathogenesisofMERS-CoVformoneofthe foundationsofMERS-CoVresearch. Inthisissue, Faragandcolleaguessummarizethepossible driversoftheemergenceofMERS-CoVanditsspillovertohumansinQatar,explainingthepotential reasonsforthecamel-to-humantransmissionofMERS-CoV[17]. ThereviewarticlebySongand colleaguesprovidesanoveralldescriptionoftheepidemiology,pathogenesis,andotherimportant aspectsofMERS-CoV[18].Widagdoandcolleaguesreviewthehostdeterminantsofthetransmission and pathogenesis of MERS-CoV, indicating that receptor DPP4 plays an important role in these processes[19].AresearcharticlebyYanandcolleaguescharacterizestheroleoflipidprofilesinthe pathogenesisandinfectivityofhumancoronaviruses,includingMERS-CoV,suggestingthatlipid metabolismmaybeinvolvedinthepropagationsofthesecoronaviruses[20].Thesereportsprovide insightsintohowMERS-CoVinfectscellsandspreadswithinandacrosshostspecies.Theyhavealso laidthefoundationsfordevelopinganimalmodels. Animalmodelsareessentialtoolsforthepreclinicalevaluationofanti-MERS-CoVcountermeasures. Dromedarycamels,alpacas,andnon-humanprimatesaresusceptibletoMERS-CoVinfection[21–23]; however,thevirusdoesnotinfectsmallanimalssuchasmice,hamsters,andferrets[24–26].Several mousemodelsthatexpresshumanDPP4(hDPP4)havebeenestablishedforMERS-CoVinfection[27–29]. Inthisissue,WidagdoandcolleaguesexaminerabbitsaspotentialhostsforMERS-CoV,showing thatMERS-CoVinfectsrabbitswithoutcausingsymptoms;theyalsoanalyzetherouteofMERS-CoV Viruses2019,11,663;doi:10.3390/v11070663 1 www.mdpi.com/journal/viruses