New Systematic review and meta-analysis identifies potential host … · 2020. 8. 27. · Systematic review and meta-analysis identifies potential host therapeutic targets in COVID-19

Systematicreviewandmeta-analysisidentifiespotentialhosttherapeutictargetsinCOVID-19.NicholasParkinson*,NatashaRodgers*,MaxHeadFourman*,BoWang,MarieZechner,MaaikeC.Swets,JohnnyMillar,AndyLaw,ClarkD.Russell!,J.KennethBaillie!,SaraClohisey!

*equalcontribution

!equalcontribution

[email protected]@roslin.ed.ac.uk

Abstract

AnincreasingbodyofliteraturedescribestheroleofhostfactorsinCOVID-19pathogenesis.Thereisaneedtocombinediverse,multi-omicdatainordertoevaluateandsubstantiatethemostrobustevidenceandinformdevelopmentoffuturetherapies.

Weconductedasystematicreviewofexperimentsidentifyinghostfactorsinvolvedinhumanbetacoronavirusinfection(SARS-CoV-2,SARS-CoV,MERS-CoV,seasonalcoronaviruses).GenelistsfromthesediversesourceswereintegratedusingMeta-AnalysisbyInformationContent(MAIC).Thispreviouslydescribedalgorithmusesdata-drivengenelistweightingstoproduceacomprehensiverankedlistofimplicatedhostgenes.

5,418genesimplicatedinhumanbetacoronavirusinfectionwereidentifiedfrom32datasets.ThetoprankedgenewasPPIA,encodingcyclophilinA.PharmacologicalinhibitionwithcyclosporineinvitroexertsantiviralactivityagainstseveralcoronavirusesincludingSARS-CoV.Otherhighly-rankedgenesincludedproposedprognosticfactors(CXCL10,CD4,CD3E)andinvestigationaltherapeutictargets(IL1A)forCOVID-19,butalsopreviouslyoverlookedgeneswithpotentialastherapeutictargets.GenerankingsalsoinformtheinterpretationofCOVID-19GWASresults,implicatingFYCO1overothernearbygenesinadisease-associatedlocusonchromosome3.PathwaysenrichedingenerankingsincludedT-cellreceptorsignalling,proteinprocessing,andviralinfections.WeidentifiedlimitedoverlapofourgenelistwithhostgenesimplicatedinARDS(innateimmuneandinflammationgenes)andInfluenzaAvirusinfection(RNA-bindingandribosome-associatedgenes).

Wewillcontinuetoupdatethisdynamicrankedlistofhostgenesasthefielddevelops,asaresourcetoinformandprioritisefuturestudies.Updatedresultsareavailableathttps://baillielab.net/maic/covid19.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprintthis version posted September 1, 2020. ; https://doi.org/10.1101/2020.08.27.20182238doi: medRxiv preprint

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

https://doi.org/10.1101/2020.08.27.20182238

http://creativecommons.org/licenses/by-nc-nd/4.0/

Introduction

TherearemultiplesourcesofinformationthatassociatehostgeneswithSARS-CoV-2viralreplication,thesubsequenthostimmuneresponseandtheensuingpathophysiology.Integratingthesesourcesofinformationmayprovidemorerobustevidenceassociatingspecificgenesandproteinswithkeyprocessesunderlyingthemechanismsofdisease.Thisisneededinordertomakeinformedjudgementsaboutnewtherapiesforinclusioninmodelstudiesandclinicaltrials.

ThepaceofnewresearchintoCOVID-19pathophysiology,includinghostdependencyfactors,immuneresponses,andgenetics,hasmadeitnearlyimpossibletoreadeveryreport.Inaddition,assessingthequalityandrelevanceofnewevidenceisdifficult,time-consuming,andrequiresahighlevelofexpertise.Informationfromdiversesourceshasvaryingquality,scale,andrelevancetohostresponsestoSARS-CoV-2.Computationalapproachescanaiddataevaluationandintegration.Simple,intuitivemethodshaveaconceptualadvantagefortranslationtodecision-making:ifboththeprocessesandresultsareeasilycomprehensible,thenitiseasierforhumanuserstotrusttheconclusions.

SARS-CoV-2isabetacoronaviruswitha30kbsingle-strandedpositive-senseRNAgenome,andisgeneticallysimilartootherhumancoronaviruses:SARS-CoV,MERS-CoVandtheseasonal‘commoncold’229E,OC43,HKU1andNL63coronaviruses.Likeallviruses,SARS-CoV-2reliesonhostmachinerytoreplicate.Hostdependencyfactorsrepresentanattractivetargetfornewtherapeutics,asevolutionofdrugresistanceisexpectedtobeslowerforhost-directedthanviral-directedtherapies.1

Treatmentdirectlytargetingviralreplicationcantargetviralproteins(e.g.remdesivir2),orhostproteinsuponwhichthevirusdepends.3Host-targetedtherapiesmayhaveanimportantroleininfectiousdiseasesingeneral,andtheonlytreatmentsofarfoundtoreducemortalityinCOVID-19-dexamethasone4-islikelytoactbytargetinghostimmune-mediatedorgandamage.5Otherhost-directedtreatments(e.g.anakinra,tocilizumab,sarilumab,mavrilimumab),repurposedfromotherindications,arecurrentlyunderinvestigation.2,6,7,8,9,10

InthisanalysiswesystematicallyidentifyandcombineexistingdatafromhumanbetacoronavirusresearchtogenerateacomprehensiverankedlistofhostgenesasaresourcetoinformfurtherworkonCOVID-19.

Toidentifyexistingliteraturewhichcouldprovideinformativedatasetsforhostgeneprioritisation,weconductedasystematicreviewofpublishedstudiesandpre-printmanuscriptspertainingtohostgeneinvolvementinhumanbetacoronavirusinfectionandassociateddisease.Resultsfromidentifiedstudies,intheformoflistsofimplicatedhostfactorgenes,werecombinedusingmeta-analysisbyinformationcontent(MAIC),3anapproachwepreviouslydevelopedtoidentifyhostgenesnecessaryforInfluenzaAvirus(IAV)replication.WehavepreviouslydemonstratedthattheMAICalgorithmsuccessfullypredictsnewexperimentalresultsfromanunseenfutureexperiment.3Ourgeneprioritisationresultsbothrecapitulateexisting



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understandingofCOVID-19pathophysiologyandhighlightkeyhostfactorsandpotentialtherapeutictargetsthathavetodatebeenlargelyoverlooked.

Methods

Meta-analysisbyinformationcontent(MAIC)

MAICallowsthecombinationofdatafromdiversesourceswithoutpriorassumptionsregardingthequalityofeachindividualdatasource.TheMAICapproachbeginswiththefollowingassumptions:

1. Thereexistsasetoftruepositives:hostgenesinvolvedinCOVID-19pathogenesis.

2. Ageneismorelikelytobeatruepositiveifitisfoundinmultipleexperiments.3. Ageneismorelikelytobeatruepositiveifitoccursinalistcontainingahigher

proportionofgeneswithsupportingevidencefrommultiplesources.4. Duetoexperimentalbiases,theevidencethatageneisatruepositiveisfurther

increasedifitisfoundacrossexperimentaltypes.

Withtheseassumptions,MAICallowsthequantificationoftheinformationcontentinagenelistbycomparingthatlisttotheresultsfromotherexperimentsthatmightreasonablybeexpectedtofindsomeofthesamegenes.Inputgenelistscanbecategorisedbydatatype(Table2),allowingcomparisonbothwithinandbetweenmethodologies.MAICproducesaweightingfactorforeachexperiment,andthisweightingisusedtocalculateascoreforeachgene.Theanalysisthenproducesafinalrankedlistofgenesbasedonthisscore,whichsummarisesthecombinedevidencefromallinputsourcesofthatparticulargenebeinginvolvedinSARS-CoV-2pathogen-hostinteraction.AfulldescriptionoftheMAICalgorithmcanbefoundinouroriginalreport.3

Dataeligibility

InclusionandexclusioncriteriaareshowninTable1.TocomplementemergingdatapertainingtothenovelSARS-CoV-2,weincludedstudiesofotherhumancoronaviruses.IncludedmethodologiesareshowninTable2.

Table1:EntryCriteria

Inclusion Exclusion

Virusstudied:SARS-CoV,SARS-CoV-2,MERS-CoV,HCoV-229E,HCoV-HOC43,HCoV-HKU1,HCoV-NL63

Candidateinvitroorinvivogene,transcriptorproteinstudiesandscreens-definedhereas<50genes,transcriptsorproteinsinvestigated

MethodologypresentinTable2 Candidate-genehumangeneticstudies <5hostsinvirusgrouporcontrolgroupin

patientstudies



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Meta-analyses,insilicoanayses,re-analysisofdatapublishedelsewhere

Table2:Methodologiesacceptedforinclusioninmeta-analysisandassociatedlabels

AcceptedMethodologies MAICcategory

CRISPRscreen CRISPRSCREEN

RNAiscreen RNAI

Protein-proteininteractione.g.yeast-2-hybridscreen

PROTEIN-PROTEININTERACTION

Hostproteinsincorporatedintovirionorviruslikeparticle

VIRUS

GeneticAssociationStudies HUMANGENETICS,NON-HUMANGENETICS

TranscriptomicsegRNA-Seq,scRNA-Seq TRANSCRIPTOMICS

Proteomicstudieseg.mass-spectrometry PROTEOMICS

Selectedgenesetscreens GENESETSCREEN

Literaturesearch

AsystematicliteraturesearchofPubMedwasconductedon28/04/2020andupdatedweeklyuntil06/07/2020.Weusedthefollowingsearchstrategy,withnodateorlanguagerestrictions:>Keywords:(“Coronavirus”OR“SevereAcuteRespiratorySyndrome”OR“MiddleEastRespiratorySyndrome”OR“Sars-CoV-2”OR“COVID-19”)AND((gene*.[Title/Abstract])OR(genom*[Title/Abstract])OR(transcript*[Title/Abstract])OR(protein*[Title/Abstract])OR(“Susceptibility”[Title/Abstract])OR(siRNA[AllFields]))

Potentiallyrelevantpre-printmanuscriptswereidentifiedbyscreeningallpaperscategorisedasCOVID-19-relatedinthebioRxivandmedRxivservers.Titlesandabstractsofallreturnedpaperswerefirstassessedforrelevanceandduplicationbyasinglememberofthereviewteam.Followingthis,full-lengthtextswereobtainedandanin-depthreviewwascarriedoutbytwofurtherreviewers,independently,inordertoconfirmeligibilityaccordingtoTable2andTable1.Incaseswhereaconsensuswasnotreached,athirdreviewerappraisedthepaper.Thismethodensuredeachpaperwasassessedforeligibilitybyaminimumofthreeindependentreviewers.Relevantdata,asshowninTable3,wasextractedfromeachreviewedpaper.

Table3:Dataextractedfromeachpublication

ExtractedInformation Examples

Virus&viruscomponent/modification SARS-CoV-2,HCoV-229E

Method/Experimentaldesign SeeTable2



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Organism Human,rodent,Non-humanprimate

Cell/tissuetype Vero6,A549,serum

Peerreviewedorpre-print peer-reviewed,pre-print

Genelistextractionandcategorisation

Relevantgenelistswereidentifiedandextracted.Datasetswereexcludedfromtheanalysiswhereinsufficientdatawereavailabletoconstructameaningfulunbiasedgenelist,forexamplewhereresultsforonlyanon-systematicallyselectedsubsetofgenesofinterestwerereported.GenelistswerecategorisedbasedonmethodologyasshowninTable2.

Genelistrankingswerepreservedwherepossible,ifsufficientnumericaldatawereavailable.Rankingswerebasedonsignificanceormagnitudeofeffect.Adjustedmeasuresofsignificance,usuallyadjusted!,wereprioritisedoverraw!and!"#$%todeterminerankingwheremultiplevalueswereavailable.Forstudiesreportingcomparisonsatmultipletimepoints,geneswererankedbasedontheminimum!acrossallcomparisons.Toexcludeirrelevantgenes,asignificanceoreffectsizethresholdwasappliedtoalllists.Thiswaseitherthethresholdusedbytheauthorsforreporting,orwherefulldatawereprovidedthiswasdeterminedasadjusted! < 0.05,|! !"#$%| > 1.96or|!"#$%| > 1.5dependingonavailablevalues.Gene,transcriptandproteinnamesoridentificationnumberswereconvertedtotheassociatedHGNCgenesymbol,oranequivalentEnsemblorRefseqsymbolwherenoHGNCsymbolexisted.Non-primategenesweremappedtotheirhumanhomologuesusingtheNCBIHomologenedatabase,11orexcludedfromtheanalysisifnohumanhomologuecouldbeidentified.

Genesetenrichmentanalysis

Rank-basedgenesetenrichmentanalysiswasperformedusingthepackageFGSEAinRversion3.5.2,withgenesrankedbyMAICscore.12!-valueswereestimatedusinganempiricalprobabilitydistributionbasedon106permutations.Genesetover-representationinthetop100geneswasanalysedbyaFisher’sexacttestasimplementedinEnrichr.13TheBenjamini-Hochbergprocedurewasusedtocontrolthefalsediscoveryrate(!"# < 0.05)forbothmethods.

Results

Systematicreviewoftheliterature

Weidentifiedatotalof31studieswithavailabledatameetingoureligibilitycriteria(12pre-printmanuscriptsand19peer-reviewedstudies),yielding32genelists(SupplementaryFigure1,SupplementaryTable1).Theincludedgenelistscomprised11rankedand21unrankedlists,in8experimentalcategories,withlistlengthsrangingfromthreeto9,967genes(median61).Thedatasetsincluded3



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geneticperturbationscreens(CRISPR,RNAiandinterferon-stimulatedgeneoverexpression),3geneticstudies(ofwhich2wereinhumans),7protein-proteininteractionstudies,7proteomicand12transcriptomicstudies.

Figure1:OverviewofMAICapproach.(A)SchematicshowingtheoperationofMAIC.Eachentityinalistisgivenascore,basedonoverlapwithotherlistsandrankwhererelevant,andeachlistisgivenaweightdeterminedbythescoresofitsconstituententities.Entityscoresareiterativelyupdatedusinglistweights,andlistweightsareupdatedusingentityscores,untilconvergenceoccurs.(B)CircularplotshowingoverlapbetweendifferentdatasourcesincludedinMAIC.Sizeofdatasourceblocksisproportionaltothesummedinformationcontent(MAICscores)oftheinputlist.Linesarecolouredaccordingtothedominantdatasource.Datasourcecategoriessharethesamecolour;thelargestcategoriesanddatasourcesarelabelled(seesupplementaryinformationforfullsourcedata).(C)Relativeinformationcontributions(determinedbysumofMAICscorecontributions)ofeachexperimentalcategorytotheevidencebaseforthetop100genesintheMAICoutput.(D)DistributionofMAICscoresbygenerank.Theshadedregionindicatestherangeofpossiblescoresforagenesupportedby



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asinglegenelistonly.Beyondranksaround700inthisstudy,genescoresapproachbaseline,indicatingtheyhavelittlecorroborativeevidence.

MAICanalysisofidentifiedstudies

Of5,418genesimplicatedinhumanbetacoronavirusinfectioninthese32datasets,4,150aresupportedbyasinglepaperonly,629hadevidencefrommorethanonesourcewithinthesameexperimentalcategory,and639aresupportedbydatafrommultiplestudytypes.Althoughextensivewithin-categoryoverlapwasseenfortranscriptomicstudies,therewaslessconcordancewithincategoriessuchasproteomicsandprotein-proteininteraction.Aswithourpreviousstudyofinfluenza,contributionsfromoneCRISPRscreendominatetheoverallinformationcontent(Figure1B).Thiswasdueinparttolistlengthandhencecontributiontoscoresformultiplelower-rankinggenes.Informationcontributionsforthetop100genesaremorebalanced(Figure1C).TheMAICscoredistribution(Figure1D)reflectsthedegreeofcross-categoryoverlap,withthehighestrankedgenessupportedbydatafromthreedistinctexperimentalcategories.

ThehighestrankinggenesandtheircontributingevidencesourcesareshowninFigure3AandSupplementaryTable2.TopgenesincludeIL1A14andothercomponentsoftheinnateandadaptiveimmunesystems(suchasCXCL10,CD4andTLR3),whichhavepreviouslybeenshowntocontributetoCOVID-19pathogenesis.Othertopgeneshavenotpreviouslyreceivedmuchattentioninthecontextofcoronavirusinfection.TheseincludePPIA(cyclophilinA),andRYBP(RING1andYY1bindingprotein),whichplayrolesinproteinfolding,transcriptionalrepression,regulationofproteasomaldegradationandapoptosis.

Anup-to-dateprioritisedlistofimplicatedgenesisavailableatbaillielab.net/maic/covid19.Wewillrepeattheanalysisregularlyasnewdatabecomeavailable.



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Figure2:Cellularfunctionsofthe100highestrankedgenesintheMAICoutput.Proteinproductsofthesegeneshavediversecellularlocationsandareassociatedwithnumerousprocessesrelevanttothevirallifecycleandhostimmunesystem.Stagesofthebetacoronaviruslifecycle:(1)Sprotein-mediatedattachmenttothecellsurface.(2)Endocytosis.(3)Membranefusionandviralgenomereleaseintothecytoplasm.(4)Assemblyofthereplication-transcriptioncomplex,translationofmRNA.(5)Viralreplicationandvirionassembly.(6)Virionmaturation,buddingandtranslocationofvesicles.



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OverlapwithgenesinvolvedininfluenzaA,ARDSandfamilialHLHpathogenesis

DeathinsevereCOVID-19isusuallyaconsequenceoflunginjuryleadingtoARDS(AcuteRespiratoryDistressSyndrome),afinalcommonpathwaythatcanoccurinanysevereacuterespiratoryinfection.HostsusceptibilityfactorsinCOVID-19maybesharedwithotherinfectionsorARDS.WecomparedtheoutputfromouranalysistoourpreviousMAICanalysisofInfluenzaAvirus.3Amongthetop500rankedgenesfromeachoutput,wefound72overlappinggenes(Figure3B),includingalargenumberofRNA-binding,ribosome-associatedandchaperonegenes.Unexpectedlyfewimmunerelatedgenesoverlapped.Thisissurprisingasbothvirusesaresingle-strandedRNAvirusesanddespitedifferinginsense,intracellularpathogendetectionmechanismsareexpectedtobesimilar.

ToexpandthisanalysiswemanuallycuratedgenesassociatedwithARDSanddeterminedtheoverlapwithourMAICoutput(SupplementaryTable4).Amongthetop500rankedgenesfromthecoronavirusMAICoutputwefoundanoverlapof13geneswiththeARDSlist(consistingof103genes)(Figure3C).Herewesawanumberofgenesassociatedwithinnateimmunityandmodulationofinflammation(TNF!,IL6,IL18,CCL2,IL1B,TLR1,IL13,NF!BIA).



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Figure3:HighestrankedgenesintheMAICoutputandoverlapwithotherconditions.(A)Heatmapofthetop50genesimplicatedinSARS-CoV-2infection,asrankedbytheMAICalgorithm.Theheatmapshowstheinformationsourcescontributingtoeachofthetopgenes,byexperimentalcategory.Fulldetailsofallscoredgenes,includingspecificstudiescontributingtoeach,aregiveninSupplementaryTable2.(B)Venndiagramofoverlapbetweenthetop500hitsfromthisstudyandthetop500hitsfromourpreviousMAICanalysisofInfluenzaAvirus.(C)Venndiagramofoverlapbetweenthetop500hitsfromthisstudyandmanuallycuratedlistsfromavailableliteratureonHLHandARDS.

Theinflammatoryprofile,includinghyperferritinaemia,observedinCOVID-19hasledtothesuggestionthataformofsecondaryhaemophagocyticlymphohistiocytosis(HLH),ahyper-inflammatorysyndrome,couldbeoccurring.15Wemanuallycurated



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genesinvolvedinthefamilialformofthissyndromeandcomparedthesewithourMAICoutput,findingnooverlap,althoughonlyelevengeneswerefoundintheliteraturetobeassociatedwithfamilialHLH.

PathwayanalysisofMAICoutput

Tobetterunderstandthebiologicalfunctionsofthemoststronglyimplicatedgenes,weperformedgenesetenrichmentanalysisintendatabasesoffunctionalannotations.Weusedtwocomplementarymethods,assessingenrichmenteitherintermsofrankdistributionacrossthewholedataset(permissive)orinover-representationinthetop100genesonly(conservative).Therewasextensiveoverlapbetweentheseapproaches(Figure4AandSupplementaryTable3).

Figure4:GeneSetEnrichmentAnalysisofMAICrankings.(A)ViolinplotsofMAICscoredistributionsoftopenrichedpathwayssignificantwithbothFGSEAandEnrichralgorithms,fromtheKEGG2019(Human)andWikiPathways2019(Human)



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databases.Highlysimilarpathwaysandirrelevantspecificdiseasetermsarenotshown.n:numberofgenesetmembersincludedintheoverallMAICoutput;NES:normalisedenrichmentscorefromFGSEA.(B):InformationcontributionbymethodologyforselectedenrichedKEGGterms.Relativecontributionsofdifferentinformationsourcesvarybetweenfunctionalannotations,butnosinglemethodologypredominatestodriveenrichment.

Functionalannotationsthatweresignificantusingbothmethodsandthatwerereflectedinresultsfrommorethanonedatabaseincludedtermsrelatedtocytokine,toll-likereceptorandT-cellreceptorsignalling,proteinprocessing,apoptosis,thecomplementsystem,VEGFsignalling,glucosemetabolismandviralinfectionssuchasinfluenzaA.Asexpected,therelativeinformationcontributionsfromdifferentexperimenttypesvariedbetweenpathways(Figure4B).Forexample,termsrelatedtocomplementandcoagulationreceivedrelativelylittlecontributionfromCRISPRscreendata(derivedfromepithelialcells)butmoreinformationfromproteomicsandexperimentsusingserumorswabsamples,whilstpathwaysrelatedtoproteinprocessinghadrelativelygreatercontributionsfromproteininteractionstudies.Inallcases,enrichedpathwaysdrewinformationfromarangeofexperimenttypes.

IntegrationofMAICoutputwithresultsfrompublishedGWAS

OneoftheprincipalapplicationsofMAICisintheinterpretationofresultsofgenome-wideassociationstudies(GWAS).Genome-wideassociationstudiesoftenimplicatealocuscontaininganumberofcandidategenesandtheprecisenatureoftheinteractionbetweengeneanddiseasemaynotbeknown.Asanexample,weappliedourresultstothelocusinchromosome3associatedwithhospitalisationduetoCOVID-19inthesoleCOVID-19GWASpublishedtodate(datafromwhichwasalsoincludedinthisanalysis).16Thislocuscontainedsixgenes(SL6A20,LTZFL1,CCR9,FYCO1,CXCR6andCXR1)thatcouldallplausiblybelinkedtoCOVID-19pathophysiologyonthebasisoftheirknownfunctions.

Ofthese,FYCO1,whichencodesaproteininvolvedinvesicletransportandautophagy,washighlyrankedinourresults(rank42).FYCO1issupportedbySARS-CoV-2-specificprotein-proteininteractionandtranscriptomicdata.CCR9(rank417)hadadditionalsupportfromasingletranscriptomicstudy,whileSL6A20,LTZFL1,CXCR6andXCR1hadlowranksinourresults,withnocorroboratingevidenceinotherstudies.

Discussion

Theinterpretationofanymeta-analysisiscriticallydependentonthecriteriaforinclusion.Inthiscase,ourobjectiveistocastthenetwide,includingarangeofdatasourcesthatarebothconceptuallyandmethodologicallydivergent.ExperimentalresultsbearinglittlerelationtothecompositeofevidencefromtheotherstudiesaredowngradedbytheMAICalgorithm,sotheeffectofirrelevant,noisy,orpoorly-conductedexperimentsisminimal.3Byusingpermissiveinclusioncriteria,togetherwithweightedmeta-analysis,wehaveidentifedkeyelementsofthehost-pathogen



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interactionandpromisingtherapeutictargetsforfurtherinvestigationandintervention.Theseincludehostfactorsinvolvedinviralreplication,andelementsoftheimmuneresponse,whichhavebeenoverlookedinthecontributingstudies(Figure2).

Keyhostfactorsrelatedtoviralentryandreplication

Coronaviruseshijackhostendomembranestofacilitateanchoringofthereplication/transcriptioncomplex.17Consistentwiththis,weobserveanover-representaionofendoplasmicreticulum-relatedgenes.Genesrelatedtothefunctionoftheendoplasmicreticulum(FAF2,ERGIC1,TENT5C,TENT5A,CFL1,STARD5)andglycosylation(MOGS,UGDH,UGGT1,PDIA6,PDIA3)areobservedalongwithanumberofchaperoneproteins(HSPB1,HSPA4,HSPA8,HSP90AA1,ST13).Manyofthesegenesarerelatedtotheunfoldedproteinresponse(UPR),astressresponseinitiatedbyaccumulationofmisfoldedproteins.FYCO1,implicatedinpublishedGWASresults,hasbeensuggestedasakeymediatorlinkingER-deriveddoublemembranevesicles,theprimaryreplicationsiteforcoronaviruses,withthemicrotubulenetwork.18

Viralentryviaspike(S)protein-mediatedmembranefusioniswellcharacterised.19Thefirststep,spikeactivation,requirescleavageviahostproteasessuchascathepsinL(CTSL,rank31).20IntheWeietal.21CRISPRscreen,knockoutofCTSLrestrictedviralproduction.CathepsinLinhibitionhasbeensuggestedasapromisingtherapeuticstrategyforCOVID-19:specificsmallmoleculeinhibitorsareinearlystagesofdevelopment,anddirectorindirectinhibitionisobservedwithanumberofapproveddrugsincludingglycopeptideantibiotics,chloroquineanddexamethasone.22ATP1A1(rank35),encodingasubunitoftheNA+/K+cotransporter,hassimilarlybeenshowntobenecessaryformembranefusionandviralentryforanumberofcoronaviruses.23InhibitionofATP1A1bycardiacglycosidessuppressedMERS-CoVinfectioninvitro.24Additionalanti-inflammatory25effectsofthesedrugsmakethemtheoreticallyattractivetherapeuticoptions,butadverseeffectsmaylimittheirpracticalapplication.

Theinterferon-stimulatedgeneLY6E(rank3),whichplaysakeyroleinenhancingcellularentrybyRNAvirusesincludinginfluenzaAvirus,26wasunexpectedlyfoundtohaveastrongrestrictingeffectonSARS-CoV-2,SARS-CoVandMERS-CoV.27Suchwidelyoppositedifferentialeffectsondifferentviruseshavebeenreportedforotherhostgenes,suchasIFITM3,RSAD2andAXL(ranked1056,1039and215respectivelybyMAIC),26andforPPIA(seebelow).

ImmuneresponsetoSARS-CoV-2

ConsistentwiththeemergingunderstandingofthepathogenesisofCOVID-19,keygenesintheinflammatoryresponsetoSARS-CoV-2infectionarehighlyrepresentedinthetop100genes.Theseincludegenesinvolvedinrecognizingthevirus(TLR3,IFIH1),activatingtheinnateimmunesystem(OAS2,HERC5,S100A9),chemotaxis(S100A9,CXCL10,CXCL8,CCL20,SAA2)andpro-inflammatorycytokines(IL1A,IL18).



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Toll-likereceptor3(TLR3)isanendosome-associatedpathogen-associatedmolecularpatternreceptor,constitutivelyexpressedintherespiratorytractandmanyimmunecells.TLR3detectsdouble-standedviralRNAandtriggersproductionoftypeIinterferonsandotherpro-inflammatorycytokines,suchasIL6(rank104)andTNF!(rank182)viaIRF3andNF-!B.28ThechemokineCXCL10(rank17)isakeysignallingmoleculeinviralimmunity,whichcouldcontributetopulmonaryinflammationaswellasaidingviralclearance.29CXCL10levelsareassociatedwithoutcomeininfluenza30andarethoughttohaveaprotectiveeffectinSARS,butaproviraleffectinHIV.31CXCL10hasbeenproposedasaprognosticmarkerfortheprogressionofdiseaseinCOVID-19,withcontinuouslyhighlevelsofCXCL10associatedwithworseoutcomes.32

ThehighrankingsofgenesassociatedwithactivationandbindingofTlymphocytes(CD4,CD3E,FGL2,LCK,SELL)arealsolikelyrelatedtotheirprognosticsignificance,aslymphopaeniaisstronglyassociatedwithpooroutcomesinCOVID-19.33,34AbsolutecountsofCD3+,CD4+andCD8+TlymphocyteshavebeenproposedasapotentialpredictorofoutcomeinsevereCOVID-19patients35withanincreaseinnumbersofthesecellsobservedduringrecovery.

Prioritisationofhostsusceptibilityfactorsastherapeutictargets

Thehighest-rankinggeneisPPIA,whichencodespeptidyl-prolylcis-transisomeraseA(PPIA,alsoknownascyclophilinA,CypA),acytosolicproteininvolvedinproteinfoldingandtrafficking,cellsignallingandT-cellactivationviathecalcineurin/NFATpathway.36CypAisapro-viralfactorforhepatitisCvirus(HCV),HIV-1,andSARS-CoV,andananti-viralfactorforIAV.37,38

ThecyclophilininhibitorcyclosporinehasinvitroantiviralactivityagainstHCV.39,40,41ThiswasalsoobservedinaHCVclinicaltrial,wherecyclosporinecombinedwithinterferon-!wasmoreefficaciousinachievingsustainedvirologicresponsethaninterferonmonotherapy.42SimilarinvitroandclinicalresultsweredemonstratedfortheCypAinhibitoralisporivir(DEBIO-015).43CypAisalsoapro-viralfactorforHIV-1andalisporivircaninhibitHIV-1replicationinvitro.44,45

Agenome-wideprotein-proteininteractionscreenidentifiedaninteractionbetweentheSARS-CoVNsp1proteinandCypA.46CyclosporineinhibitsSARS-CoVreplicationinVeroE6cells,aswellasHCoV-229E,HCoV-NL63,aviancoronavirusandfelinecoronavirus.Nsp1alsoinducedIL-2expressioninHEK293cellsthroughthecalcineurin/NFATpathway,makinginhibitionofthispathwayinterestingfrombothanantiviralandimmunomodulatoryperspective.47

ThehighrankingofIL1A(encodinginterleukin1-!)isstrikingbecausemonoclonalantibodiesagainstinterleukin1receptorareaplausibletherapeutictargetforCOVID-19.10Thispro-inflammatorycytokine,whichissynergisticwithTNF!,isconstitutivelyexpressedinepithelialcellsandisupregulatedafterSARS-CoV-2infection.48Interleukin-1receptorblockadewithanakinraisnowbeingtestedinanumberofrandomisedclinicaltrialsinCOVID-19.10



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AdvantagesandlimitationsofdataintegrationviaMAIC

TheprincipaladvantageoftheMAICapproachisthatitallowsintegrationofdatafromdiversesources.Unlikeothermethodsforgenelistcomparisonsuchasvotecountingorrobustrankaggregation,49MAICappliesadata-drivenweightingtoeachdataset,acceptsbothrankedandunrankedlists,andincludesuser-definedcategorieswhichpreventanysinglemethodfromoverwhelmingtheresults.MAICoutperformsothermethodsforpredictingantiviralgenes.3

Thismeta-analysisisrestrictedtostudiesinvolvinggenome-widehypothesesorscreeningdataforlargegenesets,anddoesnotconsiderevidencefromcandidategenegeneticstudiesorsingle-geneperturbations.Whereasinglegenehasbeeninvestigatedextensivelybutgenome-scalestudiesaresparse,ourapproachmayunderestimatetherelativestrengthofevidenceforcertaingenes.Singlegenestudies,however,arelikelytofocuspreferentiallyongenesthatfitpre-conceivedideasofdiseasepathogenesisandmaybepronetootherbiasessuchaspublicationbias,somethingwhichwemitigatedagainstinourinclusioncriteria.

GeneticperturbationdataarestillrelativelysparseforSARS-CoV-2andotherhumanbetacoronaviruses:onlyonegenome-wideCRISPRknockoutscreenandtwoothersub-genome-scalescreens(kinome-wideRNAiandinterferon-stimulatedgeneoverexpressionscreens)wereincludedinthemeta-analysis.LimiteddataofthistypecouldberesponsibleforthelowerthanexpectedrankingsforACE2(rank320),amajorfunctionalreceptorfortheSARS-CoVandSARS-CoV-2spike(S)proteins,andTMPRSS2(rank3037),aserineproteaserequiredforSproteinpriming.19,50,51WhileACE2wasidentifiedasahostdependencyfactorintheCRISPRscreen,TMPRSS2wasnot,andasneithergenewasincludedintheothertwoscreens,theeffects(orlackthereof)couldnotbeconfirmed.Theonlyothersupportiveevidenceforaroleindiseasepathophysiology,instudiesincludedhere,camefromasingletranscriptomicstudyforeach;therewasnoevidencefromprotein-proteininteraction,proteomicsorgenetics.48,52BothofthesegeneshavebeenproposedaspossibletherapeutictargetsforCOVID-19,andclinicaltrialsareunderwayfortheTMPRSS2inhibitorsnafamostatandcamostatmesylate.

Systematicreviewandmeta-analysisareroutineelementsintheassessmentofclinicalevidenceandsomefieldsingenomics,buthavebeenlesswidelyappliedtomechanisticbiology.Usingaflexibleandintuitivemethod,wehavesystematicallyreviewedandmeta-analysedhostgene-leveldatafromstudiesthataddressarangeofcomplementaryquestionsregardinghumanbetacoronavirusinfection.Thisprovidesexternalvalidationfornumeroushostgenesimplicatedinbothvirallifecycle,andimmuneresponse,andidentifiesseveralplausibletherapeutictargetswithbroadsupportfrommultiplesources.

Acknowledgements

TheauthorswouldliketoacknowledgeProf.C.WileyandProfJ.Doenchforsharingdataandtheirhelpfulcommentsonthemanuscript.



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https://doi.org/10.1056/NEJMoa2020283

https://doi.org/10.1101/2020.08.27.20182238


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https://doi.org/10.1101/2020.08.27.20182238


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3



https://doi.org/10.1101/2020.05.14.20102558

https://doi.org/10.1101/2020.05.08.20095836

https://doi.org/10.1101/2020.04.27.20081810

https://doi.org/10.1101/2020.08.27.20182238


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N



https://doi.org/10.1101/2020.05.23.20110916

https://doi.org/10.1101/2020.03.05.979260

https://doi.org/10.1101/2020.03.31.019216

https://doi.org/10.1101/2020.08.27.20182238


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https://doi.org/10.1101/2020.04.19.20068015

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https://doi.org/10.1101/2020.04.30.071274

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https://doi.org/10.1101/2020.08.27.20182238


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https://doi.org/10.1101/2020.08.27.20182238


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https://doi.org/10.1101/2020.08.27.20182238


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