β-Defensins in the Fight against Helicobacter pylori Raffaela Pero.pdf

该【β-Defensins in the Fight against Helicobacter pylori Raffaela Pero 】是由【妙玉】上传分享，文档一共【17】页，该文档可以免费在线阅读，需要了解更多关于【β-Defensins in the Fight against Helicobacter pylori Raffaela Pero 】的内容，可以使用淘豆网的站内搜索功能，选择自己适合的文档，以下文字是截取该文章内的部分文字，如需要获得完整电子版，请下载此文档到您的设备，方便您编辑和打印。:..moleculesReview-DefensinsintheFightagainstHelicobacterpyloriRaffaelaPero1,*,LorenaCoretti1,ErsiliaNigro2,3,FrancescaLembo4,SoniaLaneri4,BarbaraLombardo1,2,AuroraDaniele2,3andOlgaScudiero1,2,*ologieMediche,UniversitàdegliStudidiNapoli“FedericoII’,80131Napoli,Italy;lorena.******@(.);barbara.******@(.)2CEINGE-ologieAvanzateScarl,,80145Napoli,Italy;ersilia.******@(.);aurora.******@(.)ologieAmbientaliBiologicheFarmaceutiche,SecondaUniversitàdegliStudidiNapoli,,81100Caserta,Italy4DipartimentodiFarmacia,UniversitàdegliStudidiNapoli‘FedericoII’,ViaMontesano49,80131Napoli,Italy;******@(.);sonia.******@(.)*Correspondence:******@(.);olga.******@(.);Tel.:+39-081-7704795(.);+39-081-3737819(.)AcademicEditors:PaulaGomesandStefaniaGaldieroReceived:5January2017;Accepted:4March2017;Published:7March2017Abstract:Antimicrobialpeptides(AMPs)playapivotalroleintheinnateimmuneresponsestoHelicobacterpylori(Hp)inhumans.-Defensins,aclassofcationicarginine-richAMPs,aresmallpeptidessecretedbyimmunecellsandepithelialcellsthatexertantimicrobialactivityagainstanisms,includingGram-positiveandGram-,AMPexpressionisabletoeradicatethebacteria,--?ydiscussthepotentialuseofAMPs,eitheraloneorincombinationwithconventionalantibiotics,:defensins;Helicobacterpylori;gastricdisease;(Hp)isaGram-negative,spiral-shaped?agellatebacteriuminvolvedinseveralgastricdiseases[1].plicationsofHpinfectionincludepepticulcerdisease(10%),gastricadenocarcinoma(1%–3%),andprimarygastricmucosa-associatedlymphoidtissue(MALT)lymphoma[2].WhiletheroleofHpinthepathogenesisofpepticulcerdiseaseandancerhasbeenclari?ed,contradictoryresultshaveemergedconcerningitscorrelationwithmorbidobesity[3].Approximately,halfoftheworld’spopulationisinfectedwithHpalthoughtheprevalencediffersbetweencountriesanddependsonvariousfactorssuchasHpvirulencefactors,in?ammatoryresponses,orenviromentalin?uences,which?nallyin?uencethehost-pathogeninteractions[4].Human-defensins(HBD)playapivotalroleintheimmuneresponseofthegastrointestinalepitheliumtoHp-infection[5].InthisreviewweaimedtofocusonwhatiscurrentlyknownaboutinteractionofHpandhostfocusingonbiologicalfunctionsof-,webrie?ydiscussthepotentialuseofAMPs(Antimicrobialpeptides)-associatedA(CagA)andvacuolatingcytotoxinA(VacA)(CagPathogenicityMolecules2017,22,424;doi::..Molecules2017,22,4242of17Island,cagPAI),someofwhicharemorefrequentlyassociatedwithseveregastricin?ammation,ancer[6].CagAisintroducedintocellsthroughtheT4SS(typeIVsecretionsystem),intracellularpeptidoglycaninteractswiththerecognitionmoleculeNOD1(nucleotide-bindingoligomerizationdomain),ponentsoriginatingfromGram-(NF-B),allowingthesecretionofpro-in?,partially,?ammationviaothercagPAI-dependentmechanisms[7].VacAgeneencodesan87kDproteinthatinducesvacuolationofepithelialcells[8].,vacApresentstwoalternativeallelicvariantspartsforthesregion,encodingthesignalpeptide(s1ors2allele),intermediate(i1/i2)andmid-(m1/m2)[9].binationofsandmregionallelictypesdeterminestheproductionofthecytotoxinandisassociatedwithpathogenicityofthebacteria[10].Forexample,thevacAs1andi1allelesareassociatedwithincreasedriskofpepticulceration,atrophyandgastricadenocarcinoma[11].Theneutrophil-activatingprotein(NAP)ofHprepresentsanotherimportantfactorinvolvedinelicitingthehostTh1responsebystimulatingpro-in?ammatorycytokinesandchemokinessecretionfromneutrophilsandmonocytes[12].Moreover,HpproteinsHP0175andHP0986directlyinteractwithhosttissuesviaTLR4andTumornecrosisfactorreceptor-1,respectively[13,14].Thesevirulencefactorsarealsoinvolvedinderegulationofvariousoncogenicpathways,suchasp53,wnt/-catenin,NF-BandPI3K/Aktpathways[15].Inthe?eldofin?ammatorygastricdiseasestheresearchismainlyfocusedondysregulationoftheadaptiveimmuneresponses,includingaprimarydisturbedbarrierfunctionofthegastrictractandthesystemofinnateimmunity[16].Asamucosalsurface,?cimmunity[17].Previousstudieshavereportedtheinductionofseveralpotentantimicrobialcationicdefensinpeptidesduringtheearlystagesofinfectionwithvariousbacterialspecies[18–20].Thesepeptidesareconstitutivelyexpressedorinducedandcontributetoinnateandadaptiveimmunitythrougheffectorandregulatoryfunctions[21].SincedefensinsareeffectiveagainstGramnegativeandpositivebacteria,fungi,parasites(CryptosporidiumParvum,ToxoplasmaGondii,Trypanosomacruzi,andviruses,ponentsof?rst-linehostdefenses[22–24].Theincreasingknowledgeaboutantimicrobialpeptides(AMPs)andtheirroleininnateimmunityhasaddedimportantnewaspectstoancer[25].,wellknownsince1922whentheywerefirstisolatedfromhumantearsbyFlemingandRidley[26,27].AMPsprovideprotectionagainstenvironmentalpathogens,anisms,includingbacteria,fungi,,theyexertmultiplerolesasmediatorsofin?ammationwithimpactonepithelialandin?ammatorycellsin?uencingdiverseprocessessuchascellproliferation,immuneinduction,woundhealing,cytokinerelease,chemotaxisandprotease-,dependingonorganisms,(fewerthan100aminoacids)monfeature:chargeof+2to+9duetoanexcessofpositivelyaminoacids(.,arginineandlysine).positivecharge.:..Molecules2017,22,4243of17AMPsinteractelectrostaticallywithnegativechargesofmicrobialcellmembranes(.,phospholipids),therebyincreasingthemembranepermeabilityand?nallyresultingincelldeath[28,29].ategoriesconcerningtarget:(i)plasmamembrane–activepeptidesarethoughttoactinamultistageprocesswheretheyelectrostaticallybindtoamembranesurface,aggregatetoformsuperstructures,anddisruptmembraneintegrity;(ii)asecondgroupofpeptidesactonintracellulartargetstoinhibittranscriptional,translationalorotherprocesses;(iii)andcellwall–activepeptidestargetprecursors,mechanisms,and/oressentialintermediatesinpeptidoglycan,haride(LPS),over2500peptideshavebeenidenti?edandrecordedinthedatabaseofantimicrobialpeptide[30];usually,AMPsareclassi?edbasedonsecondarystructuralfeatures,suchascathelicidins(linear-helicalpeptides),defensins(-strandpeptidesconnectedbydisul?debonds),andbactenecins(looppeptides).Inhumans,twomaincategoriesofantimicrobialpeptideplayakeyrole:cathelicidinsanddefensins,bothsecretedbyepithelialcellsofmanytissuesasrespiratory,urogenitalandgastro-intestinaltracts[31].:TheClassi?cationDefensins,aclassofcationicAMPsargininerich,aresmallpeptideshighlyconservedduringtheevolutionfromplantstohumans[32].Theyaresecretedbyimmunecellsasneutrophils,monocytesandepithelialcellsofgastro-intestinal,pulmonary,urogenitalepithelia,skinandplacenta[33,34].anisms,Gram-positive,-negative,fungiandviruses[35]ells,:-,-and-?-pro-peptidesof94–95aminoacidsthatundergotwocleavageprocessesreleasingthematurepeptidesof29–34aminoacids[32].monfeatures:(i)shortsequence:18–50aminoacids(5–7KDa);(harge;(iii)presenceofsixcysteineresidues;(iv)threeintramoleculardisulphidebondsduetothepresenceofsixcysteines;absenceofpost-traductionalmodi?,theydifferfor:(i)thelengthofpeptidesegmentbetweenthesixcysteines;(ii)thepairingofthecysteinesthatareconnectedbydisul?debonds;(iii),-and-monancestralgene;thisprocessprobablyisduetotheevolutionaryresponseoftheimmunesystemtothecontinuousecologicalandenvironmentalchanges[36].Both-and-anizedintodistinctclusters,-defensingenefamilyconsistsof40familymembersat?vegenelociinhumansandmorethan50genesonchromosomes8,4,6,11,,genesonthechromosome8haveahighlycopyV),-defensinshavebeenisolatedtodate,buthumanshavethree--humanprimates,--defensinsarestructurallydifferentfrom-and-defensins:,thegeneencodingfor-defensinsoriginatesfromthemutatedgeneof-defensins[37].Theprecursorofthe-defensinsisashorterparalogousversionofthe-?debridgesthat,makingthestructureveryrigid,giveraisethetypicalcyclicstructure.:..Molecules2017,22,:Humana-DefensinsHuman-defensinsarearginine-richpeptides,containing29–-defensinstermedhumanneutrophilproteins1through4(HNP1-4)andhumandefensins5and6(HD5-and6).HNP1-4aresecretedbygranulocyteswhileHD5-hcells,inthecryptsofthesmallintestine.-Defensinshavebeenisolatedfromneutrophilsand,morespeci?cally,withintheazurophilicgranulesinwhichHPN1-3representaboutthe50%ofproteincontentwhileHNP4ispresentatlowconcentrations[37].DefensinsHNP1--and6arede?nedasentericdefensinsbecausetheyhcellsofthesmallintestineandintheepithelialcellsofthefemaleurogenitaltract(endometrium,andfallopiantubes)[38].Fromafunctionalpointofview,-defensinsplayakeyroleinoxygen--pro-peptides(93–100aminoacids)witha19-aminoacidsignalpeptideanda41–51aminoacidanionicpro--defensinmoleculesconsistsofthreestrandsthatconnectcysteines1–6,2–4and3–,in-defensin,butnotintheclass,thesheetis?ankedbyanhelicalsegmentofvariablelength,correspondingtotheN-[33].-DefensinsHuman-defensins(HBDs)arepeptidesofabout35aminoacidresidues,includingsixcysteineresiduesthatcreatethreedisul?debonds(1–5,2–4,30–6).Theyareexpressedpredominantlyinepithelialtissues,whichprovidethe?:,anumberof-defensinshavebeenstudied,butthebestcharacterizedareHBD1,HBD2,HBD3andHBD4[39].HBDsmanifestantimicrobialactivityagainstseveralmicrobes,includingGram-positiveandGram-negativebacteria,fungiandviruses[40,41].Invitroassaysdemonstratebroad-spectrumactivityofall-defensinsagainstGram-positiveand-negativebacteria,viruses(predominantlyenveloped),andfungi,withminimalinhibitoryconcentrationsintheg
,differentHBDsareselectiveintheirac