Antimicrobial Peptides and Human Disease (Current Topics in Microbiology and Immunology)

273 Pages·2006·2.34 MB·English

by  William M. Shafer (Editor)

306
Current Topics
in Microbiology
and Immunology
Editors
R.W.Compans,Atlanta/Georgia
M.D.Cooper,Birmingham/Alabama
T.Honjo,Kyoto·H.Koprowski,Philadelphia/Pennsylvania
F.Melchers,Basel·M.B.A.Oldstone,LaJolla/California
S.Olsnes,Oslo·P.K.Vogt,LaJolla/California
H.Wagner,Munich
W.M. Shafer (Ed.)
Antimicrobial Peptides
and Human Disease
With12Figuresand4Tables
123
WilliamM.Shafer,Ph.D.
DepartmentofMicrobiologyandImmunology
3001RollinsResearchCenter
EmoryUniversitySchoolofMedicine
Atlanta,GA30322
USA
e-mail:[email protected]
CoverIllustrationbyDawnM.E.Bowdish,DonaldJ.DavidsonandRobertE.W.Hancock
(CoverfigurereproducedwithkindpermissionofLeukemiaResearch)(thisvolume)
LibraryofCongressCatalogNumber72-152360
ISSN 0070-217X
ISBN-10 3-540-29915-7 SpringerBerlinHeidelbergNewYork
ISBN-13 978-3-540-29915-8 SpringerBerlinHeidelbergNewYork
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Preface
Microbes are in our midst soon after birth. Thankfully, the number of
harmless(andoftenbeneficial)microbesfaroutnumberthosethatwoulddo
us harm. Our ability to ward off pathogens in our environment, including
thosethatcancolonizeourexteriorand/orinteriorsurfaces,dependsonthe
integrativeactionoftheinnateandadaptiveimmunitysystems.Thisvolume
ofCTMI,entitledAntimicrobialPeptidesandHumanDisease,isdedicatedto
theroleofantimicrobialpeptides(AMPs)intheinnatehostdefensesystem
ofHomosapiens.
Theconceptthatoxygen-independentkillingsystemsofphagocyticcells
is in part attributable to the antibiotic-like action of AMPs (and antibacte-
rial proteins) stored in cytoplasmic granules served as a stimulus for AMP
researchinhumans.Unfortunately,thisearlyworkreceivedlittlenoticeand
wasover-shadowedbyinvestigationsoftheoxidativemicrobialkillingcom-
ponentsofphagocytes.Onlyahandfuloflaboratorieswereinterestedinthese
curiousantimicrobialpeptidesandproteins.However,in1980HansBoman’s
group [1] reported on the purification, characterization and antimicrobial
actionofanAMPfromanon-humansource–themothHyalophoracecropia,
providinganimportantprecedentandacatalystforthefield.Soonthereafter,
othergroupsannouncedthepurificationofAMPsfromavarietyofsources
includingvertebrates,invertebratesandplants.Itisnowapparentthatallliv-
ingsystems(includingmicrobes)havethecapacitytoproduceAMPs.Itisalso
clearthatAMPsevolvedlongbeforethedevelopmentofadaptiveimmunity
systems, and their induction following injury or infection is a highly con-
servedinnateimmuneresponsetomicrobes.Indeed,theyrepresenttheearli-
estformofhostdefense.Thus,AMPsareimportantandunderstandingtheir
contributiontohostdefensehaspromisefortheadvancementofmedicine.
With respect to humans, the groundbreaking work of Lehrer’s group
in the early 1980s [2] that characterized the alpha-defensins from human
polymorphonuclear leukocytes set the stage for the next 20years of AMP
researchasitpertainstothehumaninnateimmuneresponse.Twodecades
after the first reports of human neutrophil-derived defensins, we now have
abetter,butstillincomplete,understandingoftheAMPrepertoirepossessed
byhumans.Lessclear,however,aretheirdirectand/orindirectrolesinhost
VI Preface
defenseduringinfection.However,considerableprogresshasbeenmadein
thisareaandtheseadvancesarehighlightedinseveralchaptersofthisbook.
Using small intestinal Paneth cell alpha-defensins as model AMPs,
A. Ouellette describes in detail the synthesis and function of AMPs. This
systemservesasaverynicemodelthathasrevealedfundamentalinforma-
tionregardingtheregulationofAMPgeneexpression, AMPactivationand
secretiontotheextracellularfluidinresponsetomicrobes.Whileincreasing
evidence implicates the antibiotic-like action of AMPs as being fundamen-
tally important in host defense against infection, the immunomodulatory
activities ofthesepeptidesisbeingincreasingly appreciated.Undercertain
circumstances, these AMP immunomodulatory activities may contribute
more to overall host defense than their antimicrobial properties. It is
becoming increasingly evident that through their immunomodulatory
activitiescertainAMPsconnecttheinnateandadaptiveimmuneresponses,
providingwhatmaybeessentiallinksformaintainingtheoverallfidelityof
host defense. The wide range and importance of such activities displayed
bymembersofthedefensinandcathelicidinpeptidefamilies,thetwomain
classesofhumanAMPs,arediscussedindetailbyD.Bowdishetal.
ThecontributionofAMPstotheabilityofhumanstodefendthemselves
frominfectiousagents,especiallyonrespiratoryandalimentarymucosalsur-
faces,areplacedinoverallcontextbyB.AgerberthandG.Gudmundsson.This
chaptersetsthestageforaseriesofchaptersthatreviewandhighlightthecon-
tributionofAMPstooverallhostdefenseatmanydifferentsites,beginning
withthenotionthatAMPsareanessentialcomponentofthedefensivebarrier
imposedbyourlargestorgan(skin).AsemphasizedbyM.BraffandR.Gallo,
through their bactericidal action and immunomodulatory activities, AMPs
havegreatpromiseasfuturistictherapeuticagents.Ifthisgoalisrealized,clin-
icianswillhaveanewtreatmentoptionincombatingcommonskinpathogens
thatarefrequentlyresistanttomultipleantibiotics.Invasivebloodstreamin-
fections are often caused by bacteria that resist multiple antibiotics. These
infectionsareresponsibleforasignificantnumberofdeathsworldwideeach
year.M.YeamanandA.Bayerdescribehowneutrophil-andplatelet-derived
AMPscombatinvasivebloodstreaminfections,andtheyprovidenewinsights
astothebiologicimportanceoftheimmunomodulatoryactionofsuchpep-
tidesduringbacteremicdisease.Airbornetransmissionofpathogensisama-
jormechanismofspreadofinfectiousdiseases.AsishighlightedbyD.Laube
etal.,thepresenceandactivityofAMPsarecriticaltotheoverallhealthofthe
respiratorytract.Forinstance,thepresenceofAMPsinairwaysurfacefluid
(ASF)andtheroleofthesepeptidesinhostdefensehasbeenasubjectofgreat
interestinthattheASFfrompatientswithcysticfibrosismaybeinhibitoryfor
AMPs,whichmayexplainthesepatients’frequentandoftenlife-threatening
Preface VII
infections.StrategiesthatoptimizeAMPactivityortheapplicationofAMPs
totherespiratorysurfaceepitheliumhavepromiseinhumanmedicineforthe
treatmentoflunginfectionsthatarerefractorytoothertreatmentoptions.
OnerecurringthemeinmanyofthechaptersinthisvolumeisthatAMPs
have functions beyond antimicrobial action. In this respect, hepcidin, a
remarkableAMPandapeptidehormonethatisthehomeostaticregulatorof
ironavailability,isdiscussedbyT.Ganz.Duringinfectionandinflammation,
hepcidinsynthesisisup-regulatedand,becausetheavailabilityoffreeironis
criticalforefficientmicrobialgrowth,thepresenceandactionofhepcidincan
contribute to host defense. Sexually transmitted infections (STI), including
transmissionofthehumanimmunodeficiencyvirus,continuetobeaworld-
widepublichealthconcern.Themaleandfemalegenitaltractsaresitesfor
AMPproduction,duetotheinfiltrationofphagocyticcellsortheinducible
synthesisofAMPsbyepithelialcells.A.Coledescribestheirroleininnatehost
defenseagainstSTIswithspecialemphasisonthecontributionofgenitaltract
AMPstotheoverallhostdefensivestrategyofprotectingthevaginalmucosal
surfacefrominfection.Microbesdonotstandidlybyastheyareassaultedby
AMP.Infact,theyhavemechanismstoreduceorthwartthekillingactionof
AMP.Inthisrespect,themultiplemechanismsdevelopedbyGram-negative
and Gram-positive bacteria to escape or reduce the bactericidal action of
AMParereviewedbyA.Peschel.Inrecentyears,wehavecometoappreciate
that many pathogens grow in communities and communicate via chemical
signals as a population, and bacteria growing in one type of community
(biofilms)differsignificantlyfromthosegrowingalone(planktonicgrowth).
Thisandtherecognitionthatmicrobialbiofilmsoftenarelesssusceptibleto
antimicrobials(includingAMPs)havestimulatedresearcherstounderstand
virulencemechanismsthatoperateduringinfectiononhostorimplantsur-
faces.M.Ottoreviewsprogressinthisareaofresearchandprovidesinsights
regardingnewstrategiestodestroybiofilmformationduringinfection.
ThoseofuswhostudyAMPshavebenefitedtremendouslyfromthepio-
neeringearlyworkerswhoadvancedfundamentalknowledgeandprinciples
regarding critical topics of host defense, infectious diseases, cell biology,
biochemistry and pathology. Those accomplishments often were made
without the benefit of the instrumentation, techniques, and technologies
in molecular biology, biochemistry and cell biology that enabled the field
toprogress to its current level. We owe themmuch for their achievements,
insightsandprescience.Thisbookisdedicatedtothoseinsightfulscientists
andtheiraccomplishments.
Atlanta,2005 WilliamM.Shafer
VIII Preface
References
1. HultmarkD,SteinerH,RasmusonT,BomanHG(1980)Insectimmunity.Purifi-
cationandpropertiesofthreeinduciblebactericidalproteinsfromhemolymph
ofimmunizedpupaeofHyalophoracecropia.EurJBiochem106:7–16
2. SelstedME,HarwigSS,GanzT,SchillingJW,LehrerRI(1985)Primarystructure
ofthreehumanneutrophildefensins.JClinInvest76:1436–1439
ListofContents
α
PanethCell -DefensinSynthesisandFunction........................ 1
A.J.Ouellette
ImmunomodulatoryPropertiesofDefensinsandCathelicidins............. 27
D.M.E.Bowdish,D.J.Davidson,andR.E.W.Hancock
HostAntimicrobialDefencePeptidesinHumanDisease.................. 67
B.AgerberthandG.H.Guðmundsson
AntimicrobialPeptides:
AnEssentialComponentoftheSkinDefensiveBarrier................... 91
M.H.BraffandR.L.Gallo
AntimicrobialPeptidesVersusInvasiveInfections ......................111
M.R.YeamanandA.S.Bayer
AntimicrobialPeptidesintheAirway ...............................153
D.M.Laube,S.Yim,L.K.Ryan,K.O.Kisich,andG.Diamond
Hepcidin—APeptideHormoneattheInterface
ofInnateImmunityandIronMetabolism ............................183
T.Ganz
InnateHostDefenseofHumanVaginalandCervicalMucosae .............199
A.M.Cole
MolecularMechanismsofBacterialResistancetoAntimicrobialPeptides......231
D.KrausandA.Peschel
BacterialEvasionofAntimicrobialPeptidesbyBiofilmFormation...........251
M.Otto
SubjectIndex................................................259
ListofContributors
(Addressesstatedatthebeginningofrespectivechapters)
Agerberth,B. 67 Kisich,K.O. 153
Kraus,D. 235
Bayer,A.S. 111
Bowdish,D.M.E. 27 Laube,D.M. 153
Braff,M.H. 91
Otto,M. 251
Cole,A.M. 199 Ouellette,A.J. 1
Davidson,D.J. 27 Peschel,A. 235
Diamond,G. 153
Ryan,L.K. 153
Gallo,R.L. 91
Ganz,T. 183 Yeaman,M.R. 111
Guðmundsson,G.H. 67 Yim,S. 153
Hancock,R.E.W. 27
CTMI(2006)306:1–25
(cid:1)c Springer-VerlagBerlinHeidelberg2006
α
PanethCell -DefensinSynthesisandFunction
A.J.Ouellette((cid:1))
DepartmentofPathology&LaboratoryMedicine,MedSciD440,SchoolofMedicine,
CollegeofHealthSciences,UniversityofCalifornia,Irvine,CA92697-4800,USA
[email protected]
1 AntimicrobialPeptidesandInnateImmunity .................... 2
2 Cathelicidins ........................................... 3
3 Defensins:ACysteine-RichAMPFamily........................ 3
4 DefensinStructures ...................................... 5
5 MechanismsofDefensinBactericidalAction .................... 6
6 SitesofDefensinExpression ................................ 7
β
6.1 -Defensins ............................................ 7
α
6.2 -Defensins............................................ 7
α
7 Regulationof -DefensinBiosynthesis......................... 10
7.1 TranscriptionalRegulation ................................. 10
7.2 PosttranslationalActivation................................. 12
α
8 -DefensinsConferInnateImmunity.......................... 13
9 ConsequencesofPanethCellDefectsonHostDefense .............. 14
References.................................................. 15
Abstract Endogenousantimicrobialpeptides(AMPs)mediateinnateimmunityinev-
eryspeciesinwhichtheyhavebeeninvestigated.Cathelicidinsanddefensinsarethe
twomajorAMPfamiliesinmammals,andtheyareabundantcomponentsofphago-
cyticleukocytesandarereleasedbyepithelialcellsatmucosalsurfaces.Inthesmall
α
intestine,PanethcellsatthebaseofthecryptsofLieberkühnsecrete -defensinsand
additionalAMPsathighlevelsinresponsetocholinergicstimulationandwhenex-
α
posedtobacterialantigens.Panethcell -defensinsevolvedtofunctionintheextracel-
lularenvironmentwithbroad-spectrumantimicrobialactivities,andtheyconstitute
themajorityofbactericidalpeptideactivitysecretedbyPanethcells.Thereleaseof
Panethcellproductsintothecryptlumenisinferredtoprotectmitoticallyactivecrypt
cellsfromcolonizationbypotentialpathogensandconfersprotectionfromenteric
infection,asisevidentfromtheimmunityofmiceexpressingahumanPanethcell