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

Sequencer
SoulPicture|Kiel,IKMBUniKiel

Singlecellgenomicsisanew,high-precisionanalyticalmethod,withwhichtensofthousandsofcellsaredeterminedandpreciselycharacterizedinparallelbysequencing.ThisenabledtheresearcherstoidentifyimmaturebloodcellsinthebloodthatarecharacteristicofasevereCOVID-19course.

Three portrait photos
Bernardes/Mishra,UniKiel.

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"(PM