www .e l s e v i e r . c o m / l o c a t e / b j i d
The
Brazilian
Journal
of
INFECTIOUS
DISEASES
Review
article
The
role
of
microRNAs
in
enteroviral
infections
Jing
Wu
a,
Li
Shen
b,
Jianguo
Chen
c,
Huaxi
Xu
a,
Lingxiang
Mao
b,a,∗aSchoolofMedicine,JiangsuUniversity,Zhenjiang,JiangsuProvince,China
bDepartmentofClinicalLaboratory,ZhenjiangCenterforDiseaseControlandPrevention,Zhenjiang,JiangsuProvince,China cDepartmentofClinicalLaboratory,ZhenjiangFirstPeople’sHospital,JiangsuProvince,China
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Articlehistory:
Received11February2015 Accepted4June2015
Availableonline3September2015
Keywords:
MicroRNAs Enterovirus Infection
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ThegenusEnterovirus,amemberofthePicornavirusfamily,areRNAvirusesthatcancause poliomyelitis,hand-food-mouth disease, viral meningitis or meningoencephalitis, viral myocarditisandsoon.MicroRNAsareaclassofhighlyconserved,smallnoncodingRNAs recognizedasimportantregulatorsofgeneexpression.RecentstudiesfoundthatMicroRNAs playasignificantroleintheinfectionofEnterovirus,suchasenterovirus71,coxsackievirus B3andotherEnterovirus.Enteroviralinfectioncanaltertheexpressionofcellular MicroR-NAs,andcellularMicroRNAscanmodulateviralpathogenesisandreplicationbyregulating theexpressionlevelofviralor host’sgenes.Herein,thisreviewsummarizestheroleof MicroRNAsinenteroviralinfection.
©2015ElsevierEditoraLtda.Allrightsreserved.
Introduction
MiRNAsareaclassofhighlyconserved,smallnoncodingRNAs molecules,whichcontain18-to25-nucleotides(nt)inalmost alleukaryotes.MiRNAsregulategeneexpressionatthe post-transcriptionallevel, influence importantphysiologicaland pathologicalprocesses.1 Forexample,miR-375canpromote
beta-pancreaticdifferentiationinhumaninducedpluripotent stemcells.2Insometumordiseases,miRNAsholdapivotal
regulatoryrole. MiR-15aand miR-16can induce the devel-opment of multiple myeloma.3 MiRNAs act on mRNAs by
eithertranslation inhibitionormRNAdegradation, depend-ingontheextentofcomplementaritybetweentargetmRNA and miRNA sequence. There are two main mechanisms:
∗ Correspondingauthorat:DepartmentofClinicalLaboratory,ZhenjiangCenterforDiseaseControlandPrevention,Zhenjiang212003,
JiangsuProvince,China.
E-mailaddress:maolingxiang@aliyun.com(L.Mao).
imperfect sequence complementarity between miRNA and mRNA results in translation inhibition,4,5 and perfect sequence complementarity leads to mRNA cleavage.6 The
mechanism may beinfluenced byparameters such as the degreeofsequencehomology,1 targetsitemultiplicity,7 the
freeenergyofbinding,targetsitesecondarystructure,8 and
location ofmRNA.9 MiRNAscandown-regulate the
expres-sion oftheirtarget mRNAspredominantly bybindingto3 untranslatedregion(3UTR)of28mRNA.9,10Recentevidences
showedthatmiRNAcanalsobindtothe5UTR11orcoding
regions12ofthetargetgenetoregulategeneexpression.
More-over,onemiRNAcantargetmultiplemRNAsandonemRNA can be controlledbymultiple miRNAs.9,10,13 In conclusion,
miRNAsplayanimportantroleincelldevelopment, apopto-sis,proliferation,andsignaltransduction.14Additionally,fat
http://dx.doi.org/10.1016/j.bjid.2015.06.011
and cholesterol metabolism, nerve development, hormone secretion, and immune response may also be affected by miRNAs.15,16
ThegenusEnterovirus(EV),onegroupofthe picornavirus
family,hasthefollowingspeciesaccordingtotheInternational Committeeon TaxonomyofViruses: EV-A, which contains EV71and severalCoxsackievirusgroupA(CVA)viruses; EV-B(CoxsackievirusgroupB(CVB)viruses, CVA9,echoviruses andfew other EV);EV-C (polioviruses(PV)1–3,several CVA andfewotherEV);EV-D(EV-D68,EV-D111,EV70andEV74); EV-E, EV-F, EV-G, EV-H, EV-J, and the rhinoviruses (HRV-A, HRV-B, HRV-C). The polyprotein of EV consists of P1, P2, andP3regions,whichencodestructuralproteins(VP4-VP1) andnon-structural proteins(2A,2B, 2Cand3A,3B, 3C,3D) respectively. EV infected millions of people worldwide in recentyears,resultinginseverecomplication:HFMD,acute hemorrhagicconjunctivitis,myocarditis,aseptic meningitis, severe neonatal sepsis-like disease, acute flaccid paraly-sis, and so on.17 The best known members of the genus
EnterovirusarePV,EV7,CV,andechovirus.PVisspreadviathe fecal–oralrouteandrarelyinvadesthecentralnervous sys-tem(CNS).However,intherareinstanceswhenPVinvades the CNS, the resulting damage to motor neurons is strik-ing and often permanent. EV71 and CVA16 are common
etiologicalagents ofHFMD.18 As aneurotropicenterovirus,
EV71can violatethe patient’s nervous system and lead to severe symptoms and even to death.19,20 CV is classified
into two types, CVA and CVB. CVAs are usually prevalent in summer and mainly cause herpetic angina, skin rash, meningitis,paralytic polio lesions,fetal intrauterine infec-tion,andsuffocationduringinfectioninpregnancy.Someof CVAs,suchasCVA16,CVA4,CVA5,CVA9,CVA10,arecausative agents of HFMD as EV71. CVBs are the major pathogens of human viral myocarditis that can result in severe car-diac failureand dilated cardiomyopathy.21,22 Besidesthese,
echoviruses 4 (E4), E16, and E30 are associated with type I diabetes.23 E4,E6, E11, E13, and E30 are related toacute
meningitis/encephalitis,24,25whileE13andE11cancause
non-polioacuteflaccidparalysis.26
Accumulatedevidence hasdemonstrated thatthere are intricateinteractionsbetweenmiRNAsandviruses.MiRNAs canbeinducedandregulatedbyviruses.Forinstance,miR-101 mayserveasapotentialbiomarkerinhepatocellular carci-noma(HCC)patientsbecausemiR-101isdown-regulatedin Hepatitis B virus (HBV)-related HCC tissues.27 HBV X
pro-tein can inhibit miR-205 by hypermethylating of miR-205 promoter.28Meanwhile,manyevidencehasshowedthat
cel-lularmiRNAsplayacrucialroleinregulatingviralreplication and pathogenesisineukaryotes.For example,hsa-miR-29a down-regulatestheexpressionofHIVNefproteinand inter-fereswithHIV-Ireplication.29MiR-198caninhibitHIV-1gene
expressionandreplicationinmonocytes.30Representatively,
miR-122positivelyregulatesHCVinfectionbyincreasingHCV translationandgenomicRNAstabilitythroughdirect interac-tionswiththeviralRNAgenome.31–33Atthesametime,many
researchershavedemonstratedthatmiRNAsplayan impor-tantroleduringEVinfection.However,therearenosummary about the role of miRNAsinvolved inenteroviral infection yet. Thus,this reviewattemptsto providerecent advance-mentsabouttheroleandmachineryofmiRNAsinenteroviral
infection,inordertoincreaseourunderstandingofenteroviral pathogenesis.
The
related
investigations
of
miRNAs
and
EV71
DuetothevirulentpathogenicityofEV71,manyresearches havebeencarriedouttoexploretheroleofmiRNAsduring EV71infection.Ithasbeen verifiedthatcirculatingmiRNAs playanessentialroleinpathogen–hostinteractions. Disrup-tionofmiRNAbiogenesisbyknockingdowntheDGCR8gene, anessentialcofactorformiRNAsbiogenesis,resultedinthe inabilityofEV71tocauseinfection.Theexpressionofmany keygenesrelatedtotheinnateantiviralimmuneresponsein EV71infectedmiRNAsdepletedcellswassignificantlyhigher in comparisonwith controlcells. Ithas been showed that EV71canutilizehostmiRNAstomediatehostimmune sys-temenhancinginfection.34MiRNAcanserveasamolecular
markerforthedetectionofenteroviralinfections.Cuiand col-leaguesfoundthattheexpressionlevelof64miRNAschanged over2-foldinresponsetoEV71infectionbydeepsequencing assay,and42ofthese64miRNAswereup-regulatedandothers weredown-regulated.ManyofthesemiRNAsareassociated withmetabolicprocessandneurologicalprocesses,apoptosis, andimmuneresponseaccordingtotheresultofgeneontology analysis.35 Subsequently,byusingamiRNAarray,thisteam
reported that six miRNAs (miR-148a, miR-143, miR-324-3p, miR-628-3p,miR-140-5p,andmiR-362-3p)inserumcould dis-criminatepatientswithEVinfectionsfromhealthycontrols, andthreemiRNAs(miR-545,miR-324-3p,miR-143)could dis-tinguishEV71fromCVA16infections.36Collectively,miRNAs
arecloselyassociatedwithenterovirualinfection.
SomemiRNAscanmodulatethereplicationofEV71by tar-getingtheviralgenomedirectly.Forexample,Zhengetal.37
foundthatmiRNA-296-5pwaselevatedinEV71-infectedcells byusingacomprehensivemiRNAprofiling.Theypredictedby bioinformaticanalysisthathumanmiR-296-5pcaninhibitthe replicationofEV71bybindingtothecodingregionsofVP3and VP1proteins.ItispredictedthatmiR-23bcantargetthe con-servativesequenceofEV713UTRbybiologicalsoftware.Then itisconfirmedthatmiR-23bcaninhibitthereplicationofEV71 bytargetingEV713UTRbyluciferasereportervectorand miR-23bmimicstransfection.38Yangetal.39screenedthemiRNAs
thatmaytargetEV71genesequencebyusingonline analy-sisprograms,thenverifiedthatmiR373andmiR542-5pcould suppressthereplicationofEV71virusthroughbindingtothe 5-UTRgene.
There are alsosome miRNAsthat modulate viral repli-cation indirectly by targeting the mediator. Interferon (IFN)-mediated pathway is a crucial part of the cellular responseagainstviralinfection.TypeIIIIFNs,whichinclude IFN-1,2,and3,mediateantiviralresponsessimilartoType IIFNs.40There aresomemiRNAsthatmodulateviral
repli-cationinvolvedIFN. MiRNA-548canenhance replicationof EV71 and vesicularstomatitis virus (VSV) by targeting the 3UTR of IFN-1 and the levels of endogenous miRNA-548 are down-regulated during viral infection.41 EV71-induced
miR-146acansuppress theexpressionofIRAK1andTRAF6 which are two major elements in IFN production. Thus, EV71-induced miR-146a canenhance viral pathogenesisby
suppressingIFN production.42 Retinoic acid-induciblegene
I (RIG-I) is an intracellular RNA virus sensor that induces typeIinterferon-mediatedhost-protectiveinnateimmunity against viral infection. There is a novel positive regulator of RIG-I signaling pathway related to miRNA and EV71.43
EV71-inducedmiR-526a positively regulatestypeIIFN pro-duction and inhibits viral replication. The enhancement ofthis antiviral immuneresponse then derived from sup-pressing cylindromatosis (CYLD) expression by miR-526a. Remarkably,virus-inducedmiR-526aupregulationandCYLD downregulation can be blocked by EV71 3C protein. Cells withoverexpressedmiR-526aenhancetheresistancetoEV71 infection. In addition to this, Chang et al. investigated an apoptosis-orientedapproachbyusing mRNA-miRNA profil-ingandbioinformaticanalysis.Theypredictandverifiedthat miR-146a and miR-370 could impact twomajor apoptosis-associatedsignalingpathwaysbydecreasingSonofsevenless homolog 1 (SOS1) and growth arrest and DNA damage-inducible protein 45 (GADD45) expression, respectively. MiR-146aandmiR-370coordinatetotriggercellapoptosisin EV71infection.44EIF4Eisthecap-dependenttranslation
ini-tiationfactortoshutoffhostproteinsynthesis.MiR-141can facilitateEVinfectionincludingEV71,PV3andCVB3by tar-geting3-UTRofeIF4E.45EV71down-regulatedtheexpression
ofmiR-27asignificantly.FurtherstudyshowedthatmiR-27a couldinhibitEV71replicationbytargetingepidermalgrowth factorreceptor(EGFR).46
Moreover,toexplaintheneurologicalpathogenesisofEV71, Xu et al. did whole-genome joint mRNA and miRNA pro-fileanalysisfromEV71-infectedneuroblastomacellSH-SY5Y. Theyfound thatmiR-1246 wasspecifically up-regulated by EV71inSH-SY5Ycellsandcoulddirectlyboundwiththe3 UTRofdisk-largehomolog3(DLG3)gene,whichisassociated withneurologicaldisorders.47Thisresultmaypartlyexplain
the neurologicalpathogenesis ofEV71. We summarize the functionsandthetargetgenesofthemiRNAsinvolvedinthe infectionofEV71inTable1.
The
related
investigations
of
miRNAs
and
CVB3
CVincludingCVAandCVBmainlyleadstoherpanginaand humanheartdisease,especiallyviralmyocarditis(VMC).Many researcheshavefocusedonmiRNAsrelatedtoCVB3infection becauseCVB3isacommoncauseofmyocarditisanddilated cardiomyopathy.ToevaluatetheusefulnessofmiRNAsinthe pathogenesisofCVB3-inducedVMC,Zhangetal.analyzedthe pairedexpressionprofilesofmiRNAsandmRNAsonheart tis-suesfromCVB3-infectedmice.Theyidentifiedfivedistinctly expressedmiRNAs(miR-146a,miR-21,miR-374,miR-29a*and miR-23a),whichareinvolvedinregulatingseveralimportant innateimmuneandantiviral pathways.Thisstudyshowed thatmiRNAscanregulatethepathogenesisofCVB3-induced VMC.48
There are two miRNAs which can directly regulate the replicationofCVB3bytargetingtheviralsequence.Byusing RNAhybrid2.2andmiRanda3.2asoftware,LinlinWangetal. showedthatthereisaputativemiR-342-5ptarget(nt4989–nt 5015)inthe2C-codingregionofCVB3.Theexperimentinvitro
andamoderatemiR-342-5pabundanceinCVBinfected-Balb/c
mice validated that miR-342-5p can inhibit CVB3 replica-tion by targeting its 2C-coding region.49 Soon after, this
groupreportedthatmiR-10a*cansignificantlyaugmentthe biosynthesis and replication of CVB3 151 by targeting its nt6918–nt6941sequenceofthe3D-codingregion.Thisarticle showsthat152miRNAscouldup-regulatetheexpressionof thetargetgenes.50
TherearealsomanymiRNAswhichcanindirectlyregulate thereplicationofCVB3throughmediator.Zincfingerprotein (ZFP)-148,asa transcriptionfactor,can regulateexpression of many cell cycle regulatory genes and act as antiviral agentsformanyviruses.CVB3infectionup-regulatedmiR-203 through theactivationofPKC/AP-1cascade. Then,miR-203 up-regulated CVB3replication through targeting ZFP-148.51
MiR-155isreducedbyinfiltratinginflammatorymacrophages andTlymphocytesofbothhumanandmice.52–54MiRNA-155,
-146b, and -21 were consistently and significantly upregu-lated during VMC both in mice and human. Inhibition of miR-155 byLNA-Anti-miR invivocausedcardiac injuryand dysfunction,decreasedTlymphocyteactivationduringacute myocarditisbecausemiR-155cantargetPU.1(aninhibitorof
dendritic cell antigenpresentationtoT cells). Itisshowed miR-155 isan adversemediatorofcardiac immune activa-tionafterCVB3-inducedVMC.InvivoinhibitionofmiRNA-155 afterCVB3infectionattenuatesmyocardialinflammationand necrosis, so miRNA-155 can serve as a novel therapeutic targetforVMC.53CVB3-inducedmiR-126regulatedCVB3
repli-cation through two signal pathways, cross-talk of ERK1/2 andWnt/-cateninpathways.BytransfectingmiRNAmimics andinhibitors,itissuggestedthatmiR-126canregulatethe ERK1/2signalingpathwaysbytargetingEVH1domain contain-ing1(SPRED1).Besides,MiR-126canregulateWnt/-catenin pathwaysbytargetinglipoproteinreceptor-relatedprotein6 (LRP6)andWnt-responsiveCdc42homolog1(WRCh1),which enhancedviralcytopathogenicity.Inshort,miR-126promotes CVB3replicationthroughmediatingcross-talkofERK1/2and Wnt/-cateninsignalpathwaysbyaimingatthreespecific tar-gets: SPRED1,LRP6, and WRCH1.55 Inthe mouse modelof
CVB3-infectedVMC, miR-1measured byreal-time PCRwas upregulated upon CVB3 infection and its target gene Con-nexin43(Cx43)measuredbywesternblottingwassignificantly down-regulated.MiR-1playsanimportantroleinthe patho-physiology ofVMC and interfereswithcardiac functionby targetingCx43,themainproteinforminggap-junction chan-nelsinventricularmyocardium.56
Interestingly, there are several studies about miRNA-21 involvedinCVB3infection.InCVB3inducedmyocarditis,the expressionofmiR-21wassignificantlydecreased,while pro-grammedcelldeath4(PDCD4)wasincreased.Furtherresearch showedthatmiR-21alleviatedCVB3-inducedmyocarditisand repressedmyocardial apoptosis bytargetingPDCD4.57
MiR-21 and miR-146b were upregulated in CVB3-infected VMC. SilencingofmiR-21andmiR-146bcandecreasetheexpression levels of Th17 and ROR␥t and result in less-severe dam-age.FurtherresearchshowedthatmiR-21andmiR-146bcan regulate pathogenesis ofmurine VMCby regulating TH-17 differentiationthroughtargetingROR␥t,TH-17transcription factor.58 CVB3-upregulatedmiR-21cantriggerheartmuscle
celldamagebydisruptingcardiomyocyteinteractions.MiR-21 suppressedthelevelsofcomponentsincell–cellinteractions
Table1–MiRNAsinvolvedinEV71infection.
miRNAs Function Target Ref.
miR-296-5p Repressionofviralreplication EV71VP3andVP1-codingregion 37
miR-23b Repressionofviralreplication EV713UTR 38
miR373andmiR542-5p Repressionofviralreplication EV715UTR 39
miRNA-548 EnhancementofreplicationofEV71andVSV IFN-1 41
miR-146a Enhancementofviralpathogenesis IRAK1andTRAF6 42
miR-526a Repressionofviralreplication CYLD 43
miR-146aandmiR-370 EnhancementofEV71-inducedcellapoptosis SOS1andGADD45 44
miR-141 EnhancementofEVpropagation eIF4E 45
miR-27a Repressionofviralreplication EGFR 46
miR-1246 Contributiontotheneurologicalpathogenesis DLG3 47
Table2–MiRNAsinvolvedinCVB3infection.
miRNA Function Target Ref.
miR-146a,miR-21,miR-374,miR-29a*,miR-23a RegulationofpathogenesisofCVB3-InducedVMC Unknown 48
miR-342-5p RepressionofCVB3replication CVB32C-codingregion 49
miR-10a* Enhancementofviralreplication CVB33D-codingregion 50
MiR-203 Enhancementofviralreplication ZFP-148 51
MiR-155 Enhancementofmyocardialinflammationresponse PU.1 53
miR-126 Promotionofviralreplication SPRED1,LRP6,andWRCH1 55
miR-1 Interferenceofcardiacfunction Cx43 56
miR-21 AlleviationofCVB3-inducedmyocarditis PDCD4 57
miR-21andmiR-146b Regulationofviralpathogenesis ROP␥t 58
miR-21 Enhancementofviralpathogenesis YOD1andVCL 59
miR-21 Enhancementofviralpathogenesis SPRY1 60
miRNA VerifiedfunctionsofthemiRNA Verifiedtargets Ref.
miR-342-5p Repressionofviralreplication CVB32C-codingregion 38
miR-10a* Enhancementofviralreplication CVB33D-codingregion 39
MiR-203 Enhancementofviralreplication ZFP-148 40
MiR-155 Enhancementofmyocardialinflammationresponse PU.1 42
miR-126 Promotionofviralreplication SPRED1,LRP6,andWRCH1genes 44
miR-1 Involvedinviralmyocarditis Cx43 45
miR-21 AlleviationofCVB3-inducedmyocarditis PDCD4 46
miR-21andmiR-124b Regulationofviralpathogenesis ROP␥t 47
miR-21 Enhancementofviralpathogenesis YOD1andVCL 48
miR-21 Enhancementofviralpathogenesis SPRY1 49
throughtargeting YOD1and vinculin (VCL), whichare two componentsrelatedtotheregulationofcell–cellconnections and cardiac function. The miR-21 expressionduring CVB3 infection may contribute to the pathogenesis of VMC and theinhibitionofmiR-21canreducehostinjury.59MiR-21was
significantlyupregulatedincardiacmyocytesfromVMCand dilatedcardiomyopathy (DCM)comparedwithcontrol sam-ples.ByUsingbioinformaticsanalysis,theypredictedmiR-21 couldbindto3UTRofhomolog1(SPRY1).Furtherstudyinvitro
revealed thatthe overexpression ofmiR-21was associated withadecreaseinSPRY1 proteinexpression.These results suggestthat miR-21maycontributetothe pathogenesisof VMCtoDCMbytargetingSPRY1.60Atthesametime, miRNA-21wasalsorelatedwithothervirusesbytargetingadifferent gene.Forexample,miRNA-21wascorrelatedwithherpes sim-plexvirus(HSV)-inducedBehc¸et’sDiseaseinpatientsandin mousemodel.61Moreover,oneoftheHBVproteins,HBxcan
inducemiRNA-21expressioninHBV-inducedhepatocellular carcinoma.Then,HBV infection enhancescell proliferation
via HBx-induced miRNA-21 by targeting programmed cell deathprotein4(PDCD4)andphosphataseandtensin homo-logue(PTEN).62 Wesummarizethefunctionsandthetarget
genes of the miRNAsinvolved inthe infection ofCVB3 in
Table2.
The
related
investigations
of
miRNAs
and
other
EV
TherehavebeenmanyrecentreportsaboutmiRNAsrelated toEV71 andCVB3, including about miRNAsother EV,such asPVandHRV.TheexpressionofmiR-141isupregulatedin cellsinfectedwithPV3andCVB3,besidesEV71.45MiR-141can
shutdownhostproteinsynthesisviamediatingelF4EinPV3 andCVB3infectedcells,becauseeIF4Eisthecap-dependent translation initiation factor for shutting off host protein synthesis.34 ThereplicationofHRVisregulated bymiRNAs
as decrease of mature miRNAs reduced by DICER knock-down increases of HRV-1B replication in humanbronchial epithelial cells. Specific miRNAs binding toviral RNA dur-ingHRVinfectionisdemonstratedbyco-immunoprecipitate test with argonaute 2protein. Finally, out of this groupof miRNAs,miR-128andmiR-155,under-expressedinthe asth-matic epithelium, can affect HRV-1B replication.63 Innate
immuneresponsescan restrictviralreplication and innate immunereceptors, including toll-like receptorand retinoic acidinduciblegeneI(RIG-I)-likereceptor(RLR),whichactivate IFN system. By using a microarray, several special miR-NAs were found to be regulated by RLR signaling. One of theseRLR-induciblemiRNAs,miR-23b,targetsverylow den-sitylipoproteinreceptor(VLDLR)andLDLR-relatedprotein5 (LRP5).OverexpressionofmiR-23bandanti-miR-23bresulted indown-andup-regulatedproductionofRV1B,respectively. Ithasbeen shownthatRIG-I signalingresultsininhibition of HRV1B infection because RIG-I-inducible miR-23 targets VLDLR,areceptorforviralentryintothecell.64
Conclusions
Emerging evidence has demonstrated that miRNAs play a keyroleininteractionnetworkbetweentheEVandhost.EV infectionscanchangetheexpressionofmiRNAsinthecell. Therefore,miRNAsaffectenteroviralreplicationand patho-genesis. Some miRNAs can regulate the expression of EV genedirectly;somemiRNAscanregulateEVreplication indi-rectlybytargetingamediator.WhenmiRNAsdirectlyacton enterovirus,miRNAscancombinewiththe3UTR,5UTR,VP1, VP3, 2C-coding region, 3D-coding region ofEV to promote orsuppressEVreplication.WhenmiRNAsindirectlyinteract withEV,miRNAscanplayaregulatoryroleonvirusthrough IFN,ZFP-148,orsomeotherimmunesignalingpathwaysand soon.Inconclusion,thereareavarietyofcomplexregulated relationshipbetweenmiRNAsandEV,and miRNAshold an importantbiologicalroleinenteroviralinfection.
AlthoughmanymiRNAsareinvolvedintheregulationof enteroviralinfection,thereisstillincompleteunderstanding aboutthisregulatorynetwork.Basedontheabovereview, miR-NAscanbind tosomeregionsofEVsuchas3UTR, 5UTR, VP1,VP3,2C-codingregion,3D-codingregion.Aretheresome other EV targets of miRNAs?Although many studies have beenreportedabouttheprocessofinteractionbetween miR-NAsandEV71,CVB3,researchesaboutmiRNAsandotherEV arestilllimitedandmoreresearchesareneeded.Inaddition, futurestudiesarerequiredtoexploretheprecisemechanism bywhichmiRNAsinterfereinenteroviralinfection inorder toincrease our understanding ofthe interactions between EVandmiRNA.Forexample,EV71cancauseHFMDandlead tothedevelopmentofsevereneurologicaldiseases.However, theinvolvementofmiRNAsduringthedevelopmentofsevere neurologicaldiseasesisstillunclear.
Currently, moreand more miRNAshave great potential usefulnesstoserveasbiomarkersforthediagnosisof differ-entdiseases,suchascardiovasculardisease,65glioblastoma,66
and so on. Five miRNAs(miR-197, miR-629, miR-363, miR-132and miR-122)could distinguish varicellapatients from healthycontrolsand from patientswithBordetellapertussis,
measlesvirusandEV.67Importantly,miRNAshavea
poten-tialtherapeuticrole;SPC3649,atargetofmiR-122,isthefirst miRNAs-relateddrugtobetestedinhumanswithhepatitis C.68Thisdiscoveryopenupthepossibilitytodevelop
miRNAs-relateddrugstotackleenteroviraldiseases.Futureresearchis warrantedtoexploretheregulatorynetworkofthemiRNAs
andenterovirus,inordertoexploremiRNAsinthediagnosis andtreatmentofenteroviralinfection.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgements
Thisstudy was supportedbyScienceandTechnology Sup-port Program (SocialDevelopment) ofZhenjiang(GrantNo. SH2012052),JiangsuProvince“333”Project.
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