DNAsensorinvirusinfection脱氧核糖核酸识别受体及病毒感染文档格式.docx

DNAsensorinvirusinfection脱氧核糖核酸识别受体及病毒感染文档格式.docx

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Inordertoprotecthostfrominfectionofvirus,innateimmunehasdevelopedmechanismsofhowtodetectvirustotriggerimmuneresponse.Recently,DNAsensorhasbeenfoundasanoveltooltodetectvirus.Toll-likereceptor（TLR）9,retinoicacid-induciblegeneI（RIG-I）-likereceptors（RLRs）includingRIG-I,melanomadifferentiation-associatedgene-5（MDA5）,DNA-dependentRNApolymeraseIII（Pol-III）,DNAbindingprotein1（ZBP1）orDNA-dependentactivatorofIFN-regulatoryfactor（DAI）,IFN-induciblep200-proteinincludingp202，absentinmelanoma2（AIM2），interferon-inducibleprotein16（IFI16）havebeenidentifiedasDNAsensor[1-5].What’smore,DExDchelicaseDDX41,DHX36andDHX9,Leucine-richrepeatflightless-interactingprotein1（LRRFIP1）,Ku70wererecentlyfoundtobenovelDNAsensors[6-9].Table1showsDNAsensorsthathavebeendiscoveredsofarandwhichkindofDNAtheyrecognize.

Table1DNAsensorsandDNA

Family

DNAsensor

DNAbesensed

Reference

TLRs

TLR9

DNAwithoutmethylationatCpGmotifs

[10]

Helicase

DDX41

cytosolicDNA

[6]

DHX36

CpG-ADNA

[7]

DHX9

CpG-BDNA

RLRs

RIG-1

[3,11]

MDA5

[3]

p200-protein

p202

cytosolicdsDNA

[5]

AIM2

[12]

IFI16

cytosolicaswellasnucleardsDNA

[13]

Others

Ku70

[9]

Pol-III

cytosolicpoly（dA-dT）DNA

[2]

LRRFIP1

dsDNA

[8]

DAI（ZBP1）

CytosolicdsDNA

[4]

DNAsensorswereabletoinducetheproductionofcytokinessuchasIFNs,interleukins（ILs）andtumornecrosisfactor（TNF）topromotedefenseresponseagainstmicrobialinfection.Ofthese,typesIIFNsplayedapivotalroleinantiviralimmuneresponse.Sofar,fivesubtypesofthetypeIIFNhavebeenidentified:

IFN-α,IFN-β,IFN-δ,IFN-ω,andIFN-τ[14].Ofthese,IFN-δandIFN-τwerenotfoundinhumans.FourmaineffectorpathwaysoftheIFN-mediatedantiviralresponse:

①theMxGTPasepathway,②the2'

5'

-oligoadenylate-synthetase-directedribonucleaseLpathway,③theproteinkinaseRpathway,④theISG15ubiquitin-likepathway,whichindividuallyblockviraltranscription,degradeviralRNA,inhibittranslationandmodifyproteinfunctiontocontrolallstepsofviralreplication[15].Theywerealsopositivelylinkedtotheactivationandexpansionoflymphocytesthatwereimportantforcontrollingintracellularinfections[16].TypeIIIIFNs,includingIFN-λ1,functionallyresembledtypeIIFNsandplayedanimportantroleinantiviralresponseaswell[17].ButthetypeIandtypeIIIIFNantiviralsystemsdidnotmerelyduplicateeachotherfordifferentantiviralpotency,patternoftheirinductionanddifferentialtissueexpressionoftheircorrespondingreceptorsubunits[17].ILsinducedbyDNAsensorincludedIL-1β,IL-6,IL-12[18,19].IL-1βcontributedtohostdefenseagainstinfectionbyaugmentingantimicrobialpropertiesofphagocytessuchasmonocytes,macrophages,andneutrophilsandinitiatingTh1andTh17adaptiveimmuneresponses[20].IL-6notonlywascharacterizedasaBcellgrowthfactorandinducerofantibodyproduction,butalsoinducedneutrophilapoptosisandsubstantiallycontributedtotheresolutionofacuteneutrophilinfiltrationandtheCD4Tcelldifferentiation[21,22],suggestingthatIL-6playedapivotalroleduringthetransitionfrominnatetoacquiredimmunity.IL-12wasakeycytokineinthedevelopmentofTh1cellpolarizationandhasbeenshowntohavepotentimmunomodulatory,antitumor,andanti-infectionactivityinvitroandinvivo[23].Finally,TNFplayedanimportantroleinthedefenseagainstvirus,whichsubvertedtheelectrontransportsystemorthemitochondriaintoproductionofoxygenradicalsandkilledthemalignantcellsthatdidnotcontainorproduceprotectiveenzymes[24].ThushowDNAsensorstriggerallthesecytokineswillbediscussedinthisreview.What’smore,thisreviewwillsummarizeDNAsensorsthathavebeendiscoveredandtheirinteractionwithvirus.Besidesthese,howviruscounteractandhowhostnegativelyregulatetheeffectofDNAsensorswillbealsoconsideredinthisarticle.

2.DNAsensors

2.1.TLR9

TLRswereonekindofpatternrecognitionreceptor,whichplaysacriticalroleininnateimmune.Amongthem,TLR9hasbeenidentifiedasaDNAsensor.AsthereceptorforCpGcontainingbacterialandviralDNA,TLR9wasretainedintheendoplasmicreticulum（ER）[25-27].ItwasfoundbyBrinkmannMMetalthattheinteractionbetweentheERmembraneproteinUNC93BandTLR9

wascrucialforTLR9signaling[28].What’smore,ithasbeenreportedthatintracellularlocalizationofTLR9preventedrecognitionofselfDNAbutfacilitatedaccesstoviralDNA[29].

2.1.1DNAstructure

TLR9recognizedviralorbacterialDNAwithoutmethylationatCpGmotifs[10].Inwildtype（WT）mice,CpG-oligodeoxynucleotide（ODN）inducedastrongactivationofpulmonaryNF-κBaswellasasignificantincreaseinpulmonaryTNF-αandIL-1βmRNA/proteinwhiletheCpG-ODN-inducedinflammatoryresponsewasabolishedinTLR9-deficientmice[30].InthestudybyHaas,Tetal,theDNAsugarbackbonehomopolymeric,base-freephosphodiester（PD）2'

deoxyriboseactedasabasalTLR9agonistasitboundtoandactivatedTLR9,indicatingthatthePD2'

deoxyribosebackboneasanimportantdeterminantofTLR9activationbynaturalDNA[31].CpGDNAmovedintoearlyendosomesandwassubsequentlytransportedtoatubularlysosomalcompartment[26].AndYasuda,KetalfoundthatmacrophageactivationbyaDNA/cationicliposomecomplexrequiredendosomalacidification[32].ConcurrentwiththemovementofCpGDNAincells,TLR9redistributedfromtheERtoCpGDNA-containingstructuresthroughamodelwherebymodificationofthecytosolictailofTLR9,whichalsoaccumulatedmyeloiddifferentiationprimaryresponsegene88（MyD88）[25-27].

2.1.2Adenoviral（Ad）vector

Advector,aDNAvirus,hasbeenwidelyusedforgenetherapyapplicationsandasvaccinevehiclesfortreatinginfectiousdiseases. 

ItwasreportedthatAdvectorelicitedinnateimmuneresponsesviaTLR9andinducedIL-6andIL-12secretioninprimarymacrophagesanddendriticcells[19,33].TLR9deficiencyattenuatedtheinnateimmuneresponsetoAd,whereasTLR9blockadereducedtheacuteinflammatoryresponseafterintravenousinjectionofthevector[19,33].Interestingly,AdupregulatedTLR9geneexpressionindependentofTLR9functionfortheintravenousinjectionofluciferase-expressingAdvectorsintoMyD88-orTLR9-deficientmiceresultedinalmostcomparablelevelsofIL-6andIL-12productionandluciferaseexpressionwithwild-typemice,suggestingthatadditionalinnatesignalingpathwaysworkcooperativelywithTLR9[19,33].

CelltypehadaneffectontheimmuneresponseinducedbyTLR9afterAdinjection.Plasmacytoiddendriticcells（pDCs）recognitionofadenoviruswasmediatedbyTLR9anddependentonMyD88,whichinducedproductionoftypeIIFNswhileNon-pDCrecognitionofadenoviruswasTLRindependent[34,35].

2.1.3Baculovirus（BV）

Autographacalifornicanucleopolyhedrovirus（AcNPV）,awell-characterizedbaculoviruswasfoundtoactivateTLR9.TheinternalizationofviralDNAviamembranefusionmediatedbytheviralenvelopeglycoprotein,aswellasendosomalmaturation,whichreleasedtheviralgenomeintoTLR9-expressingcellularcompartments,wasnecessaryfortheinductionoftheinnateimmuneresponsebyAcNPV[1].MiceinoculatedintranasallywithAcNPVwereprotectedfromalethalchallengebyinfluenzavirus,whichmightbeduetotheinnateimmuneresponseactivatedbyTLR9.Itwasfoundthat①highlevelsofTNF-αandIL-6productionweredetectedinRAW264.7cellstreatedwithAcNPV;

②monocytesconsistingofmacrophageswerestronglyinducedbypreinoculationwithAcNPVandtheseactivatedimmunocompetentcellssuppressedthespreadoftheinfluenzavirusinfectioninlung

tissue[36].

2.1.4Myxomavirus（MV）

Themyxomavirus-inducedinnateimmuneresponserequiredtheendosomalDNAsensorTLR9anditsadaptorMyD88,transcriptionfactorsIFN-regulatoryfactor（IRF）5andIRF7,andthetypeIIFNpositive-feedbackloopmediatedbythetypeIIFNreceptor（IFNAR1）,whichledtotheproductionofIFN-α,IFN-β,TNF,andIL-12p70[37].ThisimmuneresponsewasindependentofthecytosolicRNAsensingpathwaymediatedbymitochondrialantiviralsignalingprotein（MAVS）,theTLR3adaptorToll/IL-1receptordomain-containingadaptor-inducingIFN-beta（TRIF）,orthetranscriptionfactorIRF3[37].

2.1.5Kilhamratvirus（KRV）

TLR9signalingpathwaysmightbeinvolvedinmediatingautoimmunediabetes.KRV,anssDNAparvovirus,induceddiabetesinlessthan