Bacteriophage

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"Phage"redirectshere.Forotheruses,seePhage(disambiguation).

Abacteriophage/bktr.i.ofed/(informally,phage/fed/)isavirusthatinfectsandreplicateswithin
abacterium.Thetermisderivedfrom"bacteria"andtheGreek:(phagein),"todevour".Bacteriophagesare
composedofproteinsthatencapsulateaDNAorRNAgenome,andmayhaverelativelysimpleorelaboratestructures.
Theirgenomesmayencodeasfewasfourgenes,andasmanyashundredsofgenes.Phagesreplicatewithinthe
bacteriumfollowingtheinjectionoftheirgenomeintoitscytoplasm.Bacteriophagesareamongthemostcommonand
diverseentitiesinthebiosphere.[1]Bacteriophagesareubiquitousviruses,foundwhereverbacteriaexist.Itsestimated
therearemorethan1031bacteriophagesontheplanet.Thatstenmilliontrilliontrillion,morethaneveryotherorganism
onEarth,includingbacteria,combined.[2]

Phagesarewidelydistributedinlocationspopulatedbybacterialhosts,suchassoilortheintestinesofanimals.Oneof
thedensestnaturalsourcesforphagesandothervirusesisseawater,whereupto9108virionspermilliliterhavebeen
foundinmicrobialmatsatthesurface,[3]andupto70%ofmarinebacteriamaybeinfectedbyphages.[4]Theyhave
beenusedforover90yearsasanalternativetoantibioticsintheformerSovietUnionandCentralEurope,aswellasin
France.[5]Theyareseenasapossibletherapyagainstmultidrugresistantstrainsofmanybacteria(seephage
Thestructureofatypicalmyovirus
therapy).[6]Nevertheless,phagesofInoviridaehavebeenshowntocomplicatebiofilmsinvolvedinpneumoniaandcystic bacteriophage
fibrosis,andshelterthebacteriafromdrugsmeanttoeradicatediseaseandpromotepersistentinfection.[7]

Contents[hide]
1 Classification
2 History
3 Phagetherapy
4 Replication
4.1 Attachmentandpenetration
4.2 Synthesisofproteinsandnucleicacid
4.3 Virionassembly
4.4 Releaseofvirions
5 Genomestructure
6 Systemsbiology
7 Intheenvironment
8 Otherareasofuse
9 Modelbacteriophages
10 Seealso
11 References
12 Externallinks

Classification [ edit ]

Bacteriophagesoccurabundantlyinthebiosphere,withdifferentvirions,genomes,andlifestyles.PhagesareclassifiedbytheInternationalCommitteeon
TaxonomyofViruses(ICTV)accordingtomorphologyandnucleicacid.

NineteenfamiliesarecurrentlyrecognizedbytheICTVthatinfectbacteriaandarchaea.Ofthese,onlytwofamilieshaveRNAgenomes,andonlyfivefamilies
areenveloped.OftheviralfamilieswithDNAgenomes,onlytwohavesinglestrandedgenomes.EightoftheviralfamilieswithDNAgenomeshavecircular
genomeswhileninehavelineargenomes.Ninefamiliesinfectbacteriaonly,nineinfectarchaeaonly,andone(Tectiviridae)infectsbothbacteriaandarchaea.

ICTVclassificationofprokaryotic(bacterialandarchaeal)viruses[1]
Nucleic
Order Family Morphology Examples
acid
Nonenveloped, Linear T4phage,Mu,PBSX,P1Punalike,P2,I3,
Myoviridae
contractiletail dsDNA Bcep1,Bcep43,Bcep78
Nonenveloped, Linear
Caudovirales Siphoviridae phage,T5phage,phi,C2,L5,HK97,N15
noncontractiletail(long) dsDNA
Nonenveloped, Linear
Podoviridae T7phage,T3phage,29,P22,P37
noncontractiletail(short) dsDNA
Linear
Lipothrixviridae Enveloped,rodshaped Acidianusfilamentousvirus1
dsDNA
Ligamenvirales
Nonenveloped,rod Linear
Rudiviridae Sulfolobusislandicusrodshapedvirus1
shaped dsDNA
BacteriophageP22,amemberof
Unassigned Enveloped,bottle Linear
Ampullaviridae thePodoviridaebymorphologydueto
shaped dsDNA
itsshort,noncontractiletail.
Nonenveloped,lemon Circular
Bicaudaviridae
shaped dsDNA
Nonenveloped,rod Circular
Clavaviridae
shaped dsDNA
Circular
Corticoviridae Nonenveloped,isometric
dsDNA
Segmented
Cystoviridae Enveloped,spherical
dsRNA
 Nucleic
Order Family Morphology Examples
acid
Nonenveloped,lemon Circular
Fuselloviridae
shaped dsDNA
Linear
Globuloviridae Enveloped,isometric
dsDNA
Circular
Guttaviridae Nonenveloped,ovoid
dsDNA
Nonenveloped, Circular
Inoviridae M13
filamentous ssDNA
Linear
Leviviridae Nonenveloped,isometric MS2,Q
ssRNA
Circular
Microviridae Nonenveloped,isometric X174
ssDNA
Circular
Plasmaviridae Enveloped,pleomorphic
dsDNA
Linear
Tectiviridae Nonenveloped,isometric
dsDNA

History [ edit ]

In1896,ErnestHanburyHankinreportedthatsomethinginthewatersoftheGangesandYamunariversinIndiahadmarkedantibacterialaction
againstcholeraandcouldpassthroughaveryfineporcelainfilter.[8]In1915,BritishbacteriologistFrederickTwort,superintendentoftheBrownInstitutionof
London,discoveredasmallagentthatinfectedandkilledbacteria.Hebelievedtheagentmustbeoneofthefollowing:

1.astageinthelifecycleofthebacteria
2.anenzymeproducedbythebacteriathemselvesor
3.avirusthatgrewonanddestroyedthebacteria.[9]

Twort'sworkwasinterruptedbytheonsetofWorldWarIandshortageoffunding.Independently,FrenchCanadianmicrobiologistFlixd'Hrelle,workingat
thePasteurInstituteinParis,announcedon3September1917,thathehaddiscovered"aninvisible,antagonisticmicrobeofthedysenterybacillus".For
dHrelle,therewasnoquestionastothenatureofhisdiscovery:"InaflashIhadunderstood:whatcausedmyclearspotswasinfactaninvisiblemicrobea
virusparasiticonbacteria."[10]D'Hrellecalledthevirusabacteriophageorbacteriaeater(fromtheGreekphageinmeaningtoeat).Healsorecordeda
dramaticaccountofamansufferingfromdysenterywhowasrestoredtogoodhealthbythebacteriophages.[11]ItwasD'Herellewhoconductedmuchresearch
intobacteriophagesandintroducedtheconceptofphagetherapy.[12]

In1969,MaxDelbrck,AlfredHersheyandSalvadorLuriawereawardedtheNobelPrizeinPhysiologyandMedicinefortheirdiscoveriesofthereplicationof
virusesandtheirgeneticstructure.[13]

Phagetherapy [ edit ]

Mainarticle:Phagetherapy

PhageswerediscoveredtobeantibacterialagentsandwereusedintheformerSovietRepublicofGeorgia(pioneeredtherebyGiorgiEliavawithhelpfromthe
codiscovererofbacteriophages,Felixd'Herelle)andtheUnitedStatesduringthe1920sand1930sfortreatingbacterialinfections.Theyhadwidespreaduse,
includingtreatmentofsoldiersintheRedArmy.However,theywereabandonedforgeneraluseintheWestforseveralreasons:

Medicaltrialswerecarriedout,butabasiclackofunderstandingofphagesmadetheseinvalid.[14]
Antibioticswerediscoveredandmarketedwidely.Theywereeasiertomake,storeandtoprescribe.
FormerSovietresearchcontinued,butpublicationsweremainlyinRussianorGeorgianlanguagesandwereunavailableinternationallyformanyyears.

TheirusehascontinuedsincetheendoftheColdWarinGeorgiaandelsewhereinCentralandEasternEurope.Thefirstregulated,randomized,doubleblind
clinicaltrialwasreportedintheJournalofWoundCareinJune2009,whichevaluatedthesafetyandefficacyofabacteriophagecocktailtotreatinfected
venouslegulcersinhumanpatients.[15]TheFDAapprovedthestudyasaPhaseIclinicaltrial.Thestudy'sresultsdemonstratedthesafetyoftherapeutic
applicationofbacteriophagesbutdidnotshowefficacy.Theauthorsexplainthattheuseofcertainchemicalsthatarepartofstandardwoundcare
(e.g.lactoferrinorsilver)mayhaveinterferedwithbacteriophageviability.[15]AnothercontrolledclinicaltrialinWesternEurope(treatmentofearinfections
causedbyPseudomonasaeruginosa)wasreportedshortlyafterinthejournalClinicalOtolaryngologyinAugust2009.[16]Thestudyconcludesthat
bacteriophagepreparationsweresafeandeffectivefortreatmentofchronicearinfectionsinhumans.Additionally,therehavebeennumerousanimalandother
experimentalclinicaltrialsevaluatingtheefficacyofbacteriophagesforvariousdiseases,suchasinfectedburnsandwounds,andcysticfibrosisassociated
lunginfections,amongothers.[17]Meanwhile,bacteriophageresearchersaredevelopingengineeredvirusestoovercomeantibioticresistance,andengineering
thephagegenesresponsibleforcodingenzymeswhichdegradethebiofilmmatrix,phagestructuralproteinsandalsoenzymesresponsibleforlysisofbacterial
cellwall.[3][4][5]

D'Herelle"quicklylearnedthatbacteriophagesarefoundwhereverbacteriathrive:insewers,inriversthatcatchwasterunofffrompipes,andinthestoolsof
convalescentpatients."[18]Thisincludesriverstraditionallythoughttohavehealingpowers,includingIndia'sGangesRiver.[19]

Replication [ edit ]

Bacteriophagesmayhavealyticcycleoralysogeniccycle,andafewvirusesarecapableofcarryingoutboth.Withlytic
phagessuchastheT4phage,bacterialcellsarebrokenopen(lysed)anddestroyedafterimmediatereplicationofthe
virion.Assoonasthecellisdestroyed,thephageprogenycanfindnewhoststoinfect.Lyticphagesaremoresuitable
forphagetherapy.Somelyticphagesundergoaphenomenonknownaslysisinhibition,wherecompletedphage
progenywillnotimmediatelylyseoutofthecellifextracellularphageconcentrationsarehigh.Thismechanismisnot
identicaltothatoftemperatephagegoingdormantandisusuallytemporary.

Incontrast,thelysogeniccycledoesnotresultinimmediatelysingofthehostcell.Thosephagesabletoundergo
DiagramoftheDNAinjection
lysogenyareknownastemperatephages.TheirviralgenomewillintegratewithhostDNAandreplicatealongwithit
process
relativelyharmlessly,ormayevenbecomeestablishedasaplasmid.Thevirusremainsdormantuntilhostconditions
deteriorate,perhapsduetodepletionofnutrientsthen,theendogenousphages(knownasprophages)becomeactive.
Atthispointtheyinitiatethereproductivecycle,resultinginlysisofthehostcell.Asthelysogeniccycleallowsthehostcelltocontinuetosurviveandreproduce,
thevirusisreplicatedinallofthecellsoffspring.Anexampleofabacteriophageknowntofollowthelysogeniccycleandthelyticcycleisthephage
lambdaofE.coli.[20]

Sometimesprophagesmayprovidebenefitstothehostbacteriumwhiletheyaredormantbyaddingnewfunctionstothebacterialgenomeinaphenomenon
calledlysogenicconversion.ExamplesaretheconversionofharmlessstrainsofCorynebacteriumdiphtheriaeorVibriocholeraebybacteriophagestohighly
virulentones,whichcausediphtheriaorcholera,respectively.[21][22]Strategiestocombatcertainbacterialinfectionsbytargetingthesetoxinencoding
prophageshavebeenproposed.[23]

Attachmentandpenetration [ edit ]

Toenterahostcell,bacteriophagesattachtospecificreceptorsonthesurfaceofbacteria,
includinglipopolysaccharides,teichoicacids,proteins,orevenflagella.Thisspecificitymeansabacteriophagecan
infectonlycertainbacteriabearingreceptorstowhichtheycanbind,whichinturndeterminesthephage'shostrange.
Hostgrowthconditionsalsoinfluencetheabilityofthephagetoattachandinvadethem.[24]Asphagevirionsdonot
moveindependently,theymustrelyonrandomencounterswiththerightreceptorswheninsolution(blood,lymphatic
circulation,irrigation,soilwater,etc.).

Myovirusbacteriophagesuseahypodermicsyringelikemotiontoinjecttheirgeneticmaterialintothecell.Aftermaking
contactwiththeappropriatereceptor,thetailfibersflextobringthebaseplateclosertothesurfaceofthecellthisis
knownasreversiblebinding.Onceattachedcompletely,irreversiblebindingisinitiatedandthetailcontracts,possibly
withthehelpofATPpresentinthetail,[4]injectinggeneticmaterialthroughthebacterialmembrane.Podoviruseslackan
elongatedtailsheathsimilartothatofamyovirus,sotheyinsteadusetheirsmall,toothliketailfibersenzymaticallyto
degradeaportionofthecellmembranebeforeinsertingtheirgeneticmaterial.
Inthiselectronmicrographof
bacteriophagesattachedtoabacterial
Synthesisofproteinsandnucleicacid [ edit ]
cell,thevirusesarethesizeandshape
Withinminutes,bacterialribosomesstarttranslatingviralmRNAintoprotein.ForRNAbasedphages,RNAreplicaseis ofcoliphageT1.

synthesizedearlyintheprocess.ProteinsmodifythebacterialRNApolymerasesoitpreferentiallytranscribesviral
mRNA.Thehostsnormalsynthesisofproteinsandnucleicacidsisdisrupted,anditisforcedtomanufactureviralproductsinstead.Theseproductsgoonto
becomepartofnewvirionswithinthecell,helperproteinsthathelpassemblethenewvirions,orproteinsinvolvedincelllysis.WalterFiers(Universityof
Ghent,Belgium)wasthefirsttoestablishthecompletenucleotidesequenceofagene(1972)andoftheviralgenomeofbacteriophageMS2(1976).[25]

Virionassembly [ edit ]

InthecaseoftheT4phage,theconstructionofnewvirusparticlesinvolvestheassistanceofhelperproteins.Thebaseplatesareassembledfirst,withthetails
beingbuiltuponthemafterward.Theheadcapsids,constructedseparately,willspontaneouslyassemblewiththetails.TheDNAispackedefficientlywithinthe
heads.Thewholeprocesstakesabout15minutes.

Releaseofvirions [ edit ]

Phagesmaybereleasedviacelllysis,byextrusion,or,inafewcases,bybudding.Lysis,bytailedphages,
isachievedbyanenzymecalledendolysin,whichattacksandbreaksdownthecellwallpeptidoglycan.An
altogetherdifferentphagetype,thefilamentousphages,makethehostcellcontinuallysecretenewvirus
particles.Releasedvirionsaredescribedasfree,and,unlessdefective,arecapableofinfectinganew
bacterium.BuddingisassociatedwithcertainMycoplasmaphages.Incontrasttovirionrelease,phages
displayingalysogeniccycledonotkillthehostbut,rather,becomelongtermresidentsasprophage.

Genomestructure [ edit ]

Giventhemillionsofdifferentphagesintheenvironment,phages'genomescomeinavarietyofformsand Diagramofatypicaltailedbacteriophagestructure

sizes.RNAphagesuchasMS2havethesmallestgenomesofonlyafewkilobases.However,someDNA
phagessuchasT4mayhavelargegenomeswithhundredsofgenesthesizeandshapeofthecapsidvariesalongwiththesizeofthegenome.[26]

Bacteriophagegenomescanbehighlymosaic,i.e.thegenomeofmanyphagespeciesappeartobecomposedofnumerousindividualmodules.These
modulesmaybefoundinotherphagespeciesindifferentarrangements.Mycobacteriophagesbacteriophageswithmycobacterialhostshaveprovided
excellentexamplesofthismosaicism.Inthesemycobacteriophages,geneticassortmentmaybetheresultofrepeatedinstancesofsitespecific
recombinationandillegitimaterecombination(theresultofphagegenomeacquisitionofbacterialhostgeneticsequences).[27]Itshouldbenoted,however,that
evolutionarymechanismsshapingthegenomesofbacterialvirusesvarybetweendifferentfamiliesanddependonthetypeofthenucleicacid,characteristics
ofthevirionstructure,aswellasthemodeofthevirallifecycle.[28]

Systemsbiology [ edit ]

Phagesoftenhavedramaticeffectsontheirhosts.Asaconsequence,thetranscriptionpatternoftheinfectedbacteriummaychangeconsiderably.For
instance,infectionofPseudomonasaeruginosabythetemperatephagePaP3changedtheexpressionof38%(2160/5633)ofitshost'sgenes.Manyofthese
effectsareprobablyindirect,hencethechallengebecomestoidentifythedirectinteractionsamongbacteriaandphage.[29]

SeveralattemptshavebeenmadetomapProteinproteininteractionsamongphageandtheirhost.Forinstance,bacteriophagelambdawasfoundtointeract
withitshostE.coliby31interactions.However,alargescalestudyrevealed62interactions,mostofwhichwerenew.Again,thesignificanceofmanyofthese
interactionsremainsunclear,butthesestudiessuggestthattherearemostlikelyseveralkeyinteractionsandmanyindirectinteractionswhoseroleremains
uncharacterized.[30]