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