2005The future of animal models of invasive aspergillosis

MedicalMycologySupplement12005,43,S115ÁS119

ThefutureofanimalmodelsofinvasiveaspergillosisT.F.PATTERSON

DepartmentofMedicine,UniversityofTexasHealthScienceCenteratSanAntonio,SanAntonio,Texas,USAThediagnosisofinvasiveaspergillosisremainsverydifficult,coupledwithlimited

treatmentoptions.Animalmodelshavebeenutilizedtoevaluateboththediagnosis

andtreatmentofinfectionandtoassessthepathogenicityandvirulenceofthe

organism.However,animalmodelshavenotbeenstandardizedandhavebeenused

inonlyalimitedfashionforgenomicevaluationinthisdisease.Extensiveefforts

areunderway

toexpandsignificantlytheAspergillusgenomicinformation.Thus,

thestandardizationofanimalmodelsofinvasiveaspergillosisiscriticaltocreatea

unifiedplatformtoenhanceevaluationofnewergenomicinformationandallow

assessmentofpathogenicityandvirulencefactors.Proposedmodels,supportedby

arecentlyawardedNationalInstitutesofHealth/NationalInstituteofAllergyand

InfectiousDiseasescontract,willbedevelopedincloseinteractionwiththe

extendedAspergilluscommunity(includingacademiaandindustry)toanswerkey

questionsinthisdisease.Thegoalofthisworkistoprovidetheframeworkto

evaluategenomictargetsinanimalmodelsinordertoimprovethediagnosisand

treatmentofinvasiveaspergillosisthatwillultimatelyresultinimprovedoutcomes

ofpatientswiththisfrequentlyfatalinfection.

KeywordsAspergillus,invasiveaspergillosis,animalmodels

Introduction

Animalmodelshavebeenutilizedtoevaluateboththe

diagnosisandtreatmentofinvasiveaspergillosis,and

havealsobeenusedtoassesspathogenicandvirulence

featuresoftheorganism[1Á3].However,thelackof

standardizationofanimalmodelsystemsinthisdisease

haslimitedtheirvalueinassessingbothvirulenceand

pathogenicityandhamperedeffortstoidentifynew

diagnosticandtherapeutictargets.Extensiveeffortsare

underwaytosignificantlyexpandtheAspergillusgeno-

micinformation;asaresult,thereisgreatpotentialfor

identifyingnewdiagnosticandtherapeuticstrategies

criticallyneededforthisoftenlethalinfection.One

approachtoimprovingAspergillusanimalmodelshas

beentheawardofacontractbytheNationalInstitutes

ofHealth/NationalInstituteofAllergyandInfectious

Disease(NIH/NIAID)toestablishandstandardizeanimalmodelsofinvasiveaspergillosis,includingmurineandlargeranimalspecieswithbothpulmonaryanddisseminatedinfection.Thisbriefreviewwilldiscussthefutureofanimalmodelsofinvasiveaspergillosis,thelimitationsofcurrentanimalmodels,andthechallengesfacedindevelopingstandardizedmodels.Theaimsandcriticalneedsforfuturemodels,particularlyinthedevelopmentofnewdiagnostictools,willalsobeoutlined.Thegoalofthisworkistoprovidetheframeworkforevaluatinggenomictargetsinordertoimprovethediagnosisandtreatmentofinvasiveaspergillosis,whichwillultimatelyresultinimprovedoutcomesforpatients.ObjectivesoffutureanimalmodelsThefuturedevelopmentofanimalmodelsofinvasive

aspergillosishasseveralkeyobjectives,asshownin

Table1.Theseincludethedevelopmentofstandardized

modelsthatallowreproducibilitybetweenlaboratories,

andbetweenserialexperimentsconductedlongitudin-

allyinthesamelaboratorywiththesameprotocols.A

numberofvariables,suchasdifferentroutesof

challenge(rangingfromintravenoustointranasalto

DOI:10.1080/13693780400029429Correspondence:T.F.Patterson,(ProfessorofMedicine),UniversityofTexasHealthScienceCenteratSanAntonio,MailCode7881,7703FloydCurlDrive,SanAntonio,TX78229-3900,USA.Tel:'12105676680;Fax:'12105673303;E-mail:patterson@uthscsa.edu.–2005ISHAM

Table1ObjectivesofAspergillusanimalmodels

.Standardizedmodel(s)

.Recapitulateshumandisease

.Reasonablecosts

.Reproducibility

.Easeofuse

.Amenabletostudiesincluding

ÁEvaluationofnoveldiagnostics

ÁEvaluationofhostresponse

ÁEvaluationoforganismvirulencefactorsthroughmolecularmanipulations

ÁInvivoexpressionanalysis

ÁEvaluationoftherapeuticcompounds

aerosolchallenge),markedlyaffecttheoutcomeofstudies[1].Inaddition,thelackofstandardizationofvariousfactors,suchasinfectinginoculum,underlyingimmunosuppression,andvirulenceofstrainstudied,havemadecomparisonbetweenlaboratoriesdifficult

[4].Thus,amajorobjectiveforfuturemodelsistohavea‘referencestandard’modelÁor,morelikely,modelsÁthathavebeenvalidatedbetweenlaboratoriesandhavebeenshowntoproduceknowncoursesofinfectionordiseaseaswellasextentofinfectionwhichcanthenbeusedforcomparativepurposes.

Anothermajorgoalforfuturemodelsisforthecourseofdiseaseinthemodeltoaccuratelyreflectclinicalinfection.Itisparticularlyimportantfordiagnosticstudiesthatthemodelrecapitulateclinicalinfection,whichappearsmostlikelytooccurafterchallengethroughanaerosolroute.However,inmostanimalmodels,widelydisseminatedinfectionoccursmoreconsistentlywithanintravenouschallenge,andinsomesettings,suchasanimmunosuppressedrabbitmodel,pulmonaryinfectionalsoresultsfollowingintravenouschallengewhichproducesacourseofinfectionthatmimicswidelydisseminatedinfection

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