COVID-19:Releaseofimmaturebloodcellsfrombonemarrowasasignatureofseveredisease
AresearchteamwiththecontributionoftheClusterofExcellencePMIhasidentifiedcelltypesinthebloodthatindicateseverediseaseprogressioninCOVID-19.
 
InseverecasesofCOVID-19disease,notonlyclassicimmunecellsplayarole.Inparticular,thereleaseofimmatureprecursorcellsfromthebonemarrowintothebloodindicatesaparticularlyseverecourseofthediseaseandcouldcontributetocomplications.ThishasbeenshownbyaninternationalresearchteaminvolvingtheDFGClusterofExcellence"PrecisionMedicineinChronicInflammation"(PMI).TheteamincludedphysiciansandresearchersfromKielUniversity(CAU),theUniversityMedicalCenterSchleswig-Holstein(UKSH)andtheUniversitiesofBonn,Cologne,Luebeck,TuebingenandNijmegenaswellastheResearchCenterBorstelLeibnizLungCenterandthe GermanCentreforNeurodegenerativeDisorders(DZNE),togetherwithcolleaguesfromthenationalDFGresearchassociationDeCOI.ThefindingshavebeenpublishedinthejournalImmunityonThursday,November26th.
InsearchofabiomarkerforasevereCOVID-19course
InfectionswiththenovelcoronavirusSARS-CoV2mayresultinhighlyheterogeneousclinicalpictures.Whilemanyoftheinfectionsaremildorevenasymptomatic,thediseasecanbecomelife-threatening,especiallyinolderpeople.Intheseseverecases,otherorganssuchastheheartorkidneyscanbeaffectedinadditiontothelung.Aimmunologicalmisfiringplaysanimportantrole,butfindingsareaccumulatingthatdamagetosmallbloodvesselsandover-activatedbloodclottingaredecisivefactorsforaseverecourse.OneofthemostcommondirectcausesofdeathfromCOVID-19isbloodclotsinthelungs.
"Despitenumerousstudies,weactuallyknowrelativelylittleaboutthecourseofthediseaseovertime.Whichcelltypesplayanimportantrolehereandwhen?Andcanweidentifyearlymolecularsignaturesinthebloodthatpointtoseverecourseofthediseaselateron?Thesewerequestionsweaskedourselvesatthebeginningandwegotsurprisinganswers,"explainsoneoftheleadauthorsofthestudy,ProfessorPhilipRosenstiel,DirectoroftheInstituteforClinicalMolecularBiology(IKMB)attheCAUandtheUKSHandmemberofthesteeringcommitteeoftheClusterofExcellencePMI.
Twoimmaturebloodcelltypescharacteristicofseverecourse
TheteamexaminedbloodsamplesfromCOVID-19patientswhowerehospitalisedattheuniversityhospitalsinKiel,Bonn,CologneandNijmegen.Inagroupof14patients,circulatingbloodcellswereanalysedinatimeseries.Bloodsamplesfromhealthypeoplewereusedasacomparison."Thespecialfeatureisthatwewereabletoanalysehundredsofthousandsofcellsinparallelwiththehelpofso-calledsinglecellgenomicsandwerethusabletoidentifyrarecelltypes,"explainsDr.JoanaPimentaBernardes,youngscientistoftheClusterofExcellencePMIandpostdocattheIKMB,whoisoneofthefirstauthorsofthestudytogetherwiththeothertwoyoungresearchersDr.FlorianTran,ClinicianScientistoftheClusterofExcellencePMI,andDr.NehaMishra.Mishra,whoisalsoresearchingattheIKMBasapostdoc,explainsfurther:"Togetherwithotherdatasuchasclinicallaboratoryvaluesandmeasurementsofinflammatorymessengers,wewereabletocreateakindoffingerprint,asignature,ofthealteredfunctioningofthesecellsandtrackitovertime".
SignaturesoftwoimmaturecelltypesarethereforeparticularlycharacteristicofsevereCOVID-19disease:plateletprecursorcells,so-calledmegakaryocytes,andimmatureredbloodcells."Thisisparticularlysurprisingbecausetheseprecursorcellsarenormallynotinthebloodbutinthebonemarrow,wheretheymatureasneeded,"explainsTran."Weknowofsuchprogenitorcellsbeingwashedoutintothebloodofseriouslyillpatients,forexampleinbacterialsepsis(bloodpoisoning).ThishasnotyetbeendescribedforCOVID-19,"Trancontinues.  
"Withthehelpofhigh-precisioncellulargenomicanalyses,wewereabletodrawaverydetailedpictureofthecellularchangesthroughoutthecourseofthedisease.Whilepreviouslywemainlylookedatimmunecells,wewerenowabletofindcelltypesthathadpreviouslybeenoverlooked,"saysJoachimSchultze,professorattheUniversityofBonnandresearchgroupleaderattheDZNE,oneofthelastauthorsofthestudy.
PossibleexplanationforcoagulationproblemswithCOVID-19found
Thescientistsgainedimportantinsightsfromagroupof39COVID-19patientswhohadbeentreatedintheintensivecareunitinNijmegen,i.e.hadparticularlyseverecoursesofdisease.Inthisgroupofpatients,asignatureofthemegakaryocytesandredbloodcellprogenitorcellswasparticularlystronginpatientswhodiedofthediseasecomparedtopatientswhorecovered."Themegakaryocytesreflectawell-knownCOVID-19problem:bloodplateletsareresponsibleforbloodcoagulation.OneofthemostcommondirectcausesofdeathfromCOVID-19iscoagulationproblems.Theemergency-activatedmegakaryocytesinthebloodmayproduceplateletsthataggregatemoreeasilyandthusleadtothecoagulationproblems,"assumesRosenstiel.Theincreaseinredbloodcellprogenitorcellsindicatesalackofoxygenandisknownasanemergencyreactioninseverelungdiseases.
Togethertosuccess
Thestudyhasbeenmadepossiblebythenationwideconsortium-the"GermanCOVID-19OMICSInitiative"(DeCOI)-andwascarriedoutincooperationwithpartnersfromthe"HumanCellAtlas",aninternationalconsortiumforsinglecellanalysis."Itwasonlythroughthisteamworkthatthecomplexanalysesandinterpretationofthedatacouldbemasteredintheshorttimeavailable,"saysSchultze,whoisalsothecoordinatoroftheDeCOIconsortium.
"Withthepresentwork,wehavenowcreatedthebasisforvalidatingnovelbiomarkersatanearlystageofCOVID-19diseasetoidentifypatientsatriskforaseverecourseofthedisease.Thiswouldenableustoimprovethecareofparticularlyseverelyaffectedpatientsevenmorespecifically,"saysProfessorStefanSchreiber,DirectoroftheClinicforInternalMedicineI,UKSH,CampusKiel,DirectorattheIKMBandspokespersonoftheClusterofExcellencePMI."IamparticularlypleasedthatthreeyoungresearchersfromthePMIClusterofExcellencehavebeensignificantlyinvolvedinthisworkasleadauthors,includingoneofourClinicianScientists.Thisshowshowtheyoungresearchersintheclusterarealreadydoingexcellentresearchwithrelevanceforsociety.
AboutDeCOI
TheGermanCOVID-19OMICSInitiative(DeCOI)isaGermannationalnetworkofnumerousgenomeresearchersfrommorethan22institutions.Intheconsortium,theycombinetheirexpertiseandsequencinginfrastructuretomakeascientificcontributiontothemanagementoftheCOVID-19pandemic.DeCOIisbasedontheDFG-fundednetworkofNext-Generation-Sequencing(NGS)competencecenters,whichbringstogetherexpertiseinsequencingandNGSdatageneration.TheGermanHumanGenomePhenomenonArchive(GHGA)andtheNFDI4MicrobiotaConsortiumaretheothermajorfoundingconsortiaofDeCOI,offeringextendedexpertiseindatamanagementanddataanalysis.
ScientificContact:
Prof.Dr.PhilipRosenstiel
InstituteforClinicalMolecularBiology
KielUniversityandUniversityMedicalCenter(UKSH),CampusKiel
+49431500-15111
p.rosenstiel@mucosa.de
Singlecellgenomicsisanew,high-precisionanalyticalmethod,withwhichtensofthousandsofcellsaredeterminedandpreciselycharacterizedinparallelbysequencing.ThisenabledtheresearcherstoidentifyimmaturebloodcellsinthebloodthatarecharacteristicofasevereCOVID-19course.
Thefirstauthorsofthestudy,fromleft:Dr.NehaMishra,PostdocatIKMB,KielUniversityandUKSH.Dr.JoanaPimentaBernardes,PostdocattheIKMB,KielUniversityandUKSH.Dr.FlorianTran,ClinicianScientistoftheClusterofExcellencePMIattheIKMB,KielUniversityandUKSH,andtheClinicforInternalMedicineI,UKSH,CampusKiel.
Originalpublication:
J.P.Bernardes*,N.Mishra*,F.Tran*etal:Longitudinalmulti-omicsanalysesidentifyresponsesofmegakaryocytes,erythroidcellsandplasmablastsashallmarksofsevereCOVID-19trajectories.Immunity(2020).doi.org/10.1016/j.immuni.2020.11.017 *Theseauthorscontributedequally.
AbouttheClusterofExcellencePMI
TheClusterofExcellence"PrecisionMedicineinChronicInflammation"(PMI)isbeingfundedfrom2019to2025throughtheGermanExcellenceStrategy(ExStra).Itsucceedsthe"InflammationatInterfacesCluster,whichwasalreadyfundedintwoperiodsoftheExcellenceInitiative(2007-2018).Around300membersfromeightinstitutionsatfourlocationsareinvolved:Kiel(KielUniversity,UniversityMedicalCenterSchleswig-Holstein(UKSH),MuthesiusUniversityofFineArtsandDesign,KielInstitutefortheWorldEconomy(IfW),LeibnizInstituteforScienceandMathematicsEducation(IPN)),Lbeck(UniversityofLbeck,UniversityMedicalCenterSchleswig-Holstein(UKSH)),Pln(MaxPlanckInstituteforEvolutionaryBiology)andBorstel(ResearchCenterBorstel-LeibnizLungCenter).
Thegoalistotranslateinterdisciplinaryresearchfindingsonchronicinflammatorydiseasesofbarrierorganstohealthcaremoreintensively,aswellastofulfilpreviouslyunsatisfiedneedsofthepatients.Threepointsareimportantinthecontextofsuccessfultreatment,andarethereforeattheheartofPMIresearch:theearlydetectionofchronicinflammatorydiseases,thepredictionofdiseaseprogressionandcomplications,andthepredictionofindividualresponsestotreatment.
Pressoffice
fbuhse@uv.uni-kiel.de+49(0)431/8804682https://precisionmedicine.de
ClusterofExcellence "PrecisionMedicineinChronicInflammation"
ScientificOffice
Head:Dr.habil.SusanneHolsteinPostal
Christian-Albrechts-Platz4,24118Kiel,Germany
Contact:SonjaPetermann
 +49(0)431880-4850,fax:+49(0)431880-4894
spetermann@uv.uni-kiel.de
Twitter:PMI@medinflame
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