Success of Wildlife Disease Treatment Depends on Host Immune Response

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Success of Wildlife Disease Treatment Depends on Host Immune Response

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Success of Wildlife Disease Treatment Depends on Host Immune Response
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ORIGINALRESEARCH published:11April2017 doi:10.3389/fevo.2017.00028 FrontiersinEcologyandEvolution|www.frontiersin.org 1 April2017|Volume5|Article28 Editedby: BenL.Phillips, UniversityofMelbourne,Australia Reviewedby: SergioAndrsEstay, AustralUniversityofChile,Chile EugeneB.Postnikov, KurskStateUniversity,Russia *Correspondence: BrookeMaslo brooke.maslo@rutgers.edu Specialtysection: Thisarticlewassubmittedto PopulationandEvolutionary Dynamics, asectionofthejournal FrontiersinEcologyandEvolution Received: 03February2017 Accepted: 23March2017 Published: 11April2017 Citation: MasloB,Gignoux-WolfsohnSAand FeffermanNH(2017)Successof WildlifeDiseaseTreatmentDepends onHostImmuneResponse. Front.Ecol.Evol.5:28. doi:10.3389/fevo.2017.00028 SuccessofWildlifeDiseaseTreatmentDependsonHostImmuneResponseBrookeMaslo 1,2 ,SarahA.Gignoux-Wolfsohn 1 andNinaH.Fefferman 3,4 1 Ecology,Evolution,andNaturalResources,Rutgers,TheSt ateUniversityofNewJersey,NewBrunswick,NJ,USA, 2 RutgersCooperativeExtension,NewJerseyAgriculturalEx perimentStation,Rutgers,TheStateUniversityofNewJers ey, NewBrunswick,NJ,US, 3 EcologyandEvolutionaryBiology,UniversityofTennessee ,Knoxville,TN,USA, 4 NationalInstitute forMathematicalandBiologicalSynthesis,UniversityofT ennessee,Knoxville,TN,USA Infectiousdiseasessignicantlythreatenmanywildlifep opulations.Proposedtreatments oftenfailtoconsiderresultingimpactsonnaturalhostdef ensemechanismsandongoing infectionrisks.Wedemonstratetheimportanceofpriorkno wledgeofhostdefenses bymodelingoutcomesofvarioustreatmentregimesonbatpop ulationsinfectedwith white-nosesyndrome(WNS),adiseasethathascauseddecline sinmultipleNorth Americanspecies.Despitedifferencesinspeciessuscepti bilitytothecausativefungus, howhostsrespondtoandsurviveinfectionremainsunclear. Weexplorethreepotential host-defensemechanisms:upregulationoftheresponsivei nnateoradaptiveimmune systems,andrapidevolutionthatenablesevolutionaryres cue.Wedemonstratethat treatmentcanaccelerateextirpation(relativetoinactio n)ifhostsaredefendedby responsiveimmunity;whereas,treatmentcancausepopulat ionsundergoingevolutionary rescuetoregainpopulationviabilityfaster.Weconcludet hatsuccessfultreatmentof wildlifediseasesmustrstconsiderhowindividualsrespo ndtoandsurviveinfection. Keywords:batconservation,diseasetreatmentmodeling,fung alpathogen,wildlifedisease,whitenosesyndrome, wildlifediseasemanagementINTRODUCTIONInfectiousdiseasehistoricallyhasnotbeenconsideredam ajorcauseofspecies'extinctionand, therefore,diseasemanagementhasthusfarremainedalowpri orityrelativetootherconservation actions( Fisheretal.,2012;Pullinetal.,2013 ).Mountingevidencesuggests,however,thatthe inuenceofinfectiousdiseaseonextinctionriskhasbeenl argelyunderestimatedandthatthe coupledeectsofanthropogenicforcesonhostsanddiseaseswi llgreatlycontributetoourglobal biodiversitycrisis( Smithetal.,2009;McCallum,2012 ).Humaninuencesdrasticallyalterthe ecologicallandscapeinwhichpathogensandpotentialhostsin teract( Burgeetal.,2014 ),increasing bothhostsusceptibilitytoinfectionandpathogenvirulence ( Brearleyetal.,2013;Beckeretal., 2015 ).Anthropogenicclimatechangeandglobalizationhaveexpan dedthenaturalrangeofmany pathogensand/ortheirsuiteofhostspecies,releasingthemf romco-evolutionaryforcesthatmay havemaintainedlower-virulencestrains(e.g., BrasierandBuck,2001 ).Climatechangeisespecially consequentialforfungalpathogens,whicharebecomingincr easinglyheat-tolerantandthusableto infectpreviouslyprotectedendothermicanimals( RobertandCasadevall,2009;Garcia-Solacheand Casadevall,2010 ).Theunprecedentedfrequencyofdiseaseemergence( Harvelletal.,2002;Fisher etal.,2012 )andthestrengthofimpactsonwildpopulations( Daszaketal.,2000 ),increasinglypoint totheimportanceofsuccessfulmitigationofdiseaseinspeci es'conservation.

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Masloetal. WhiteNoseSyndromeTreatmentModeling Advancesinantibiotics,fungicides,andprobioticsmake eectivetreatmentofwildlifediseasesmoreachievabletha n ever.However,whilelabexperimentsorshort-termeldtrial s mayproducepromisingresults(e.g., Cornelisonetal.,2014 ), deploymentofagiventreatmentstrategymayhaveunforeseennegativeconsequencesonthehostpopulation,especiallyifho st responsetothepathogen(oritsremoval)isnotconsideredinadvance.Therefore,itiscriticaltofullyevaluatehost-pa thogen interactionspriortothedeploymentofatreatmentstrategy. Speciesbroadlymitigatepathogenexposureintwoways: eitherthroughanimmunologicalresponseattheindividualleveloranevolutionaryresponseatthepopulationlevel(orboth).Immunologicalresponsescanbeinnateoradaptive,andtheactivationofeithercanhavedierentconsequencesonthehost.Theinnateimmunesystemisoftenarstlineofdefense,identifyinginvadingpathogensusingpatter n recognitionreceptorstosetosignalingcascades(i.e.,To ll pathway, Laietal.,2009 )andresultingeneralresponsessuch asinammationandingestionofpathogensbymacrophages(e.g., Rizzettoetal.,2013 ).Theadaptiveimmunesystem ismorespecialized,usingantigen-speciccellstorecogniz e individualpathogensandmemorycellstomountresponsesuponrepeatedexposure(notethisadaptationisindividualnotevolutionary, Hebartetal.,2002;Romani,2004 ).Incontrast, anevolutionaryresponseactsatthepopulationlevel,wherebypathogenexposurecausessteepdemographicdecline,inducinganintenseselectivepressurethatfavorssurvivalofindivi duals withaspecicgeneticsignature(i.e.,resistance).Apopulati on consistingofprimarilyresistantindividualscouldrevertt o positivegrowthwithouthumanintervention,aphenomenonknownas evolutionaryrescue ( Gonzalezetal.,2013 ),but maybenetfromtargetedtreatmentwhileatlowpopulationsize( MasloandFeerman,2015 ).Thesestarkdierencesin potentialdisease-defensivemechanismssuggestthepossibi lity forequallysignicantdierencesinlong-termpopulationeect s oftreatment.Todemonstratehowoverlookingthesepotentia l dierencescancompromiseconservationeorts,weconsideracurrentlyunfoldingcasestudy:treatmentofwhite-nosesyndrome(WNS)inNorthAmericanbats. Inthe10yearsfollowingWNSemergence,thedisease hascausedseveredeclinesinseveralbatspeciesineasternNorthAmerica( Langwigetal.,2015a ).Theconservation communityhasmadesignicantstridesinunderstandingthi s previouslyunknowndiseaseofbats,includingidenticatio n ofthecausativeagent, Pseudogymnoascusdestructans ( Lorch etal.,2011 ). P.destructans isnon-nativetoNorthAmerica andappearstohavebeentransportedbyhumansfromitsendemicrangeinEurope( Puechmailleetal.,2011 ).Thefungus colonizesbatsduringanimmunosuppressedtorpor,butwhileEuropeanbatstolerateinfection( Puechmailleetal.,2011 ),nave NorthAmericanbatsexperienceadisruptionofphysiologicalhomeostasisleadingtomeasureablepopulationdeclines( Willis etal.,2011;Verantetal.,2014 ).Severityofthesedeclineshas createdasenseofurgencyforconservationinterventionin the formofchemicalorbiologicalcontrol(e.g.,fungistaticv olatile organiccompounds; Cornelisonetal.,2014 ),probiotics(e.g., Chengetal.,2016 ),orsyntheticcompounds(e.g., Raudabaugh andMiller,2015 )toeitherpreventpathogenexposuretonave populationsorreducediseaseintensityininfectedpopulations PopulationdeclinesduetoWNSvaryamongspecies( Frick etal.,2015 ),anddriversofobservedsurvivalpatternsremain unclear.Forexample, Myotislucifugus (littlebrownbat)survival reboundedmarkedlyintheyearsfollowingdiseaseemergence( Masloetal.,2015 )suggestingarapidevolutionaryresponse ( MasloandFeerman,2015 ).However, M.lucifugus exposedto P.destructans alsoexhibitelevatedexpressionofgenesrelated totheresponsiveinnateimmunesystem( Fieldetal.,2015 ).In mammalianfungalinfections,innateimmunityisthoughttobeparticularlyimportantinregulatinginfectionandsuppressin g memoryTcellstoavoidpotentiallydamaginginammation( Bacheretal.,2014 ). Toexploretreatmentimpactsonpopulationrecoveryunder eachofthepossibledisease-defensemechanisms,weappliedtoanexistingmodelsetpredictingWNS-infectedpopulationdynamics( MasloandFeerman,2015 ),asuiteofantifungal treatmentregimesinformedbytheconservationcommunity(WNSworkshop,July2015).Scenariosvariedintreatmentecacyandtheproportionofremnantpopulationstreated.Forsimplicity,weconsideronlytheresponsiveinnateimmunesystem,whichisupregulateduponpathogenexposure,andnotthebaselineinnateimmunesystem,whichprotectsthehostindiscriminatelyandcanbeassumedtoactequallyinalloftheconsideredscenarios.Weevaluatepersistencetimeofthepopulationundereachscenario,anddeterminetheminimumpopulationsizeforpopulationsundergoinganevolutionaryresponse.WhiletheseresultsmayinformdiscussionsoftreatmentforWNSinbatpopulations,ourbroadergoalistodemonstratetheneedforconsiderationofdisease-defensemechanismsatplayinanyinfectedpopulationbeingconsideredfortreatment-basedconservationactions.METHODSHostResponse-BasedPopulationViabilityModels MasloandFeerman(2015) recentlymodeledthepopulation dynamicsof Myotislucifugus undergoingresponsiveimmunityor evolutionaryrescueinthefaceofWNS(summarizedbelow).T he evolutionaryrescuemodelmakestheconservativeassumptionthatphenotypicrobustnesstoWNSwasbaseduponaBooleanprotectivegeneticprole.Batswithinanuninfectedpopulatio n wereeitherentirelyrobust, r, orsusceptible, wt, toWNS-induced mortality.Usingpublishedorestimatedvitalratesfrombef ore ( M wt and M r )andafter( CM wt and CM r ) P.destructans introduction ( Fricketal.,2010b;Masloetal.,2015 ), MasloandFeerman (2015) parameterizedfourtwo-stageLefkovitchmatrices( Morris andDoak,2002 ),eachrepresentingpopulationgrowthofone geneticsegmentofthepopulationinboththeuninfectedandinfectedstate: S j B j F j S a B a F a S j S a FrontiersinEcologyandEvolution|www.frontiersin.org 2 April2017|Volume5|Article28

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Masloetal. WhiteNoseSyndromeTreatmentModeling where S representssurvivalof M.lucifugus ; B representsthe proportionoffemalesbreeding;andthesubscripts j and a indicatevaluesfor1st-yearoradultbats,respectively.The yset 1st-yearbatsurvivalasaconstantproportion(0.47)ofadultsurvival( Fricketal.,2010b ),andheldmaternity( m )constant at F D 1,as M.lucifugus typicallyproduceasinglepupperyear ( Barclayetal.,2003 ). Startingwithaninitialpopulationvectorof5,000total individuals,theyestimatedinitialprevalenceoftherobus t geneticproleinthepopulationtobe 0 andthensplitthe initialdemography N total ,0 intotwocorrespondinginitialvectors N wt ,0 and N r ,0 suchthat N r ,0 D 0 N total ,0 and N wt ,0 D 1 0 / N total ,0 .ThisapproachdeviatedfromtraditionalPVA, whichwouldapplyasinglepopulationprojectionmatrixtoasinglestatevectorrepresentingthecurrentstage-base d demographyofthepopulation. MasloandFeerman(2015) thenprojectedpopulationgrowthintheabsenceofdiseasebyindependentlyapplyingtheappropriatematrixtoeachvectortoobtainthepopulationvectorforthenextyear: M wt N wt t D N wt t C 1 and M r N r t DN r t C 1 MasloandFeerman(2015) then computedtherealizedtotalpopulationvector N wt t C 1 CN r t C 1 andresultinggrowthrate. Themodelassumesenvironmentalcontaminationforan entirehabitat(e.g.,hibernaculum)with100%infectionfo llowing contamination.Theydene I t tobethepercentofthepopulation infectedinyear t andassumethattherateofexposure/infection inahibernaculumisindependentofgeneticrobustness.Usin g theseprobabilitiesandmatrices,theythencomputedthesubpopulationsinyear t C 1 withinasinglepopulationas thesumofindividualsthatarewildtypeanduninfected:. 1 I t / M wt N wt t ,robustanduninfected: 1 I t / M r N r t ,wild typeandinfected: I t CM wt wt t ,androbustandinfected: I t CM r r t Additionally,0.1%oftheospringfromsameprolepairs spontaneouslymutatetotheotherprole(i.e., wt wt results inaRobustospring),and r wt resultsin50%ofeachprole. Assumingrandommatingamongadults MasloandFeerman (2015) “corrected”eachoftheprojectedpopulationvectorsby subtractingtheospringwithdierentgeneticprolesfromth e projectedpopulationvectorassociatedwiththematrixreleva nt fortheparents,andaddingthemtotheospringinthevectorassociatedwiththeappropriatesubpopulationfortheresultingjuvenile. Underevolutionaryrescue,theresultingtotalpopulation vectorineachyearwasthesumoftheindividualswithineachsubpopulation,andthestabilizedgrowthrate( D 1.05)was representativeoftheshiftingproportionofgeneticrobustne ss withinthepopulation( MasloandFeerman,2015 ).Under responsiveimmunity,themodelprojectedasinglestatevector( N D 5000)representingpre-WNSstage-baseddemographic structurethroughasingleprojectionmatrix(parameterizedwithsurvivalestimatesgeneratedfrompopulationcountsofmultipleinfectedhibernaculawithintherstthreeyearsof WNS emergence; Fricketal.,2010a ).Themodeloutputpredicted continuedpopulationdeclinesstabilizingat D 0.89after3years. Forthecurrentanalysis,weseparatedtheacquiredimmune responseintoadaptiveandinnateimmunityandusedbothpublishedandestimatedvitalrates.Bothprovideprotection againstmortalityforindividualsthatsurvivedinitialex posure, butadaptiveimmunityconferslife-longindividualprotecti on, whereastheinnateimmuneprotectionislostintheabsenceofcontinuedpathogenexposure.Individualswithadaptiveimmunitywerethereforemodeledinthesamewayas( Masloand Feerman,2015 ).Incontrast,treatedandre-exposedindividuals withinnateimmunitysueredthesameinitialmortalityrisk s fromre-exposureasthoughtheyhadneverpreviouslybeenimmune(thoughiftheysurvived,theywouldagainbeprotectedthroughoutthedurationoftheircontinuousexposure).Inallotherways,thispopulationwasalsomodeledasin Masloand Feerman(2015) ( Figure1 ).Notethatthisrepresentationof innateimmunitycanvaryeitherindose-responsecurves,ori n physiologicalstateoftheindividuals.However,wedoassum e thatrapidityoftheinnateresponseisnotitselfconsistentfora n individualovertime.Wemakethisassumptionbecausesuchaconsistentresponsewouldlikelyhaveageneticcomponentandbeconsideredapotentialmechanismforevolutionaryrescue thuscoveredbythatscenario.TreatmentRegimesWeappliedasuiteoftreatmentregimestothethreehostresponsescenarios( Figure2 ),makingthefollowingassumptions basedoncurrenttreatmentresearch:(1)treatmentapplicatio n occursjustpriortoorduringthehibernationperiod;(2)noimmigration/emigrationoccursaftertreatmentdeployment ;and (3)treatmentsuppresses P.destructans growthforasingle hibernationseason.Inthepulsedmodel( Figure2 ),batsare treatedinthe1st,5th,and10thyearfollowingWNSarrival. We modeledconstanttreatmentapplicationregimes,beginning5or15yearsfollowingWNSarrivalatasite.Wealsoexaminedtheimpactsofanintervaltreatmentregime,wherebatsaretreat ed annuallybetween5and15yearsfollowingWNSarrival.Wemodeledthedemographicimpactsofeachtreatmentregimefortreatmentsthatwere25,50,75or100%eectiveandwereappliedto25,50,75or100%ofthepopulation.Weassumedaquasi-extinctionthresholdof150individuals,belowwhichapopula tion wasconsideredextirpated.Ifapopulationrevertedtopositivegrowth,wecalculatedthetimerequiredfortheabundancetoreachitsminimumviablepopulationsize(assumedtobe2,500individualsbaseduponareviewofniteratesofincreaseatWNS-infectedhibernaculaofvarioussizes; MasloandFeerman, 2015 ). RESULTSModelresultspredictthatpopulationsexhibitingaresponsiveimmunereactionafterinitialpathogenexposurepersistfor13yearswithouttreatmentapplication( Figure3 ).Regardless oftreatmenteectivenessortheproportionofthepopulationtreated,allpopulationspersistindenitelywhentreatmentisappliedannuallybeginninginYear5ofaWNSepizootic.Incontrast,beginningtreatmentinYear15resultsinapersiste nce timeofonly13yearsforpopulationsexhibitingresponsiveimmunity. Pulsedtreatmentsresultinexpeditedextirpationof populationswithimmunitywithin10–21years,withmore FrontiersinEcologyandEvolution|www.frontiersin.org 3 April2017|Volume5|Article28

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Masloetal. WhiteNoseSyndromeTreatmentModeling FIGURE1|Flowchartofthemodelundereachscenario:(A) evolutionaryrescueforwildtypeindividuals, (B) evolutionaryrescueforrobustindividuals, (C) adaptiveimmunityforall(wildtype)individuals,and (D) innateimmunityforall(wildtype)individuals.Populatio nvitalrates(survivalandreproduction)forjuvenileand adultlittlebrownbatsundereachscenarioareindicatedbe lowtheowchart. FrontiersinEcologyandEvolution|www.frontiersin.org 4 April2017|Volume5|Article28

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Masloetal. WhiteNoseSyndromeTreatmentModeling FIGURE2|Hypotheticaltreatmentregimesforbatcoloniesinfec ted withwhite-nosesyndrome. Pulsedtreatmentsoccurinthe1st,5th,and 10thyearfollowingdiseaseemergence.Constant5andConst ant15 treatmentsoccurannuallybeginninginYears5and15,respe ctively.Interval treatmentsoccurannuallybetweenthe5thand15thyearfoll owingdisease emergence. eectivetreatmentsdecreasingyearsofpersistence,apartic ularly strongtrendforinnateimmunityscenarios.Intervaltreat ments increasethepersistencetimeofpopulationswithadaptiveimmunitybytwoto11yearswhen > 50%ofthepopulationis inoculatedattreatmentecaciesof 50%,andpersistencetime generallyincreaseswithincreasingtreatmenteectivenes sand proportionofpopulationtreated.However,intervaltreatment s ofpopulationswithinnateimmunityonlydrasticallyincreas e persistencetimewhentheentirepopulationistreatedwith 75%ecacy. Atlowtreatmentecacies(25–50%),theproportionofthe populationtreatedminimallyimpactstheresultingpersistenc e timeofeachtreatmentregimeacrossallhostresponses.Aseectivenessincreases,treatingalargeproportion(75–100%)ofthepopulationcanhaveappreciablepositiveornegativeimpactsonpersistencetime,extendingitfor21yearswhenanintervaltreatmentisappliedtoapopulationwithadaptiveimmunity,ordecreasingitto4yearswhenapulsedtreatmentisappliedtoapopulationwithinnateimmunity. Allpopulationsundergoingevolutionaryrescuerevert topositivegrowthbetween5and11yearsafterdiseaseemergenceandpersistindenitelyregardlessoftreatmentregime,eectiveness,ortheproportionofpopulationtreated( Figure3 ).Withnointervention,apopulationundergoing evolutionaryrescuereachesitslowestsizeof626individu als in10yearsandispredictedtoreturntoanabundanceof2,500individualswithin39years.ImplementingconstantannualtreatmentsbeginninginYear15reducesthattimefra me minimally(1–2years)acrossalltreatmentecacies,regar dlessof theproportionofthepopulationtreated( Figure4 ),andincreases theminimumpopulationsizeonlymarginallyto686individuals Atlowtreatmentecacies(25–50%),theproportionofthepopulationtreateddoesnotdrasticallyalterthetimerequir ed forapopulationtoachieveitsminimumviablepopulationsize(1–8years).However,treatingatleast75%ofthepopulationannuallystartinginYear5,onceeveryveyears(pulsed),or in Years5–15canincreasetheabsoluteminimumpopulationsizeby35–84%.At75–100%eectiveness,treatingmoreindividualsinapopulationcansignicantlyreducethetimerequiredforabundancetoreach2,500individuals,particularlyifthetreatmentisappliedannuallybeginninginYear5orbetweenYears5–15.Treating100%ofthepopulationwitha100% FIGURE3|Persistencetimeforahibernatingbatpopulationif 0,25, 50,75or100%ofthepopulationistreatedwithanagentthati s0,25, 50,75,and100%effective. Resultsareshownforbatsexhibiting: (A) evolutionaryrescue; (B) adaptiveimmunity;and (C) responsiveinnate immunity.Dottedlinesrepresenttheyearstowhichpopulat ionswillpersistif notreatmentisapplied. FrontiersinEcologyandEvolution|www.frontiersin.org 5 April2017|Volume5|Article28

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Masloetal. WhiteNoseSyndromeTreatmentModeling FIGURE4|Batsundergoingevolutionaryrescueunderdiffere nttreatmentregimesdisplaydifferencesinthe:(A) timeuntilthepopulationreachesits minimumviablepopulationsizeof2,500individuals; (B) proportionofresistantindividualswithinthepopulation whenitreachesitsminimumviablepopulationsize; (C) populationsizeatitsinectionpoint(justpriortoreversi ontopositivegrowth);and (D) yearafterWNSinwhichthepopulationreachesthisminimums ize. eectivetreatmentunderthesetwoscenarioscanincreaseth e populationtoitsminimumviablepopulationsizeinaslittleasnineyears( Figure4 ). Importantly,theproportionofresistantbatswithinthe populationof2,500individualsremainsabove99%inallbutfou r cases.AnnualtreatmentbeginninginYear5ofeitherallbat s FrontiersinEcologyandEvolution|www.frontiersin.org 6 April2017|Volume5|Article28

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Masloetal. WhiteNoseSyndromeTreatmentModeling treatedat75%eectivenessor75%ofthebatstreatedwitha10 0% eectiveagentreducestheproportionofresistantbatsto83%.Treatingallbatswitha100%eectiveagentannuallybeginnin g inYear5orbetweenYears5and10allowsnon-resistantbatstopersist,thusreducingtheproportionofresistantbatsto31 % ( Figure4 ). DISCUSSIONImplicationsforBatConservationForbatsundergoingeithertypeofimmuneresponse,annualtreatmentbeginningearlyinthediseasephasemaybeextreme ly eectiveinreversingdemographicdeclineandcreatingaposit ive growthtrajectory.However,long-termtreatmentofmultipl e batpopulationspresentsseverallogisticalchallenges.Trea tments applieddirectlytobatswouldrequiresignicantnumbersofindividualstobecapturedatleastonceeachyear(treatment s maynotlastafullhibernationseason).Traditionalbatcapt ure methods(e.g.,harptraps,mistnests)maynotguaranteetreatmentofeven25%ofthepopulationinanygivenyear.Activelytreatingbatsduringthehibernationperiodwouldincreasethelikelihoodthattheappropriatethresholdnumberofbatsaretreatedbutwoulddisturbhibernatingpopulationsunlessapassivedeliverysystemisimplemented.Hibernaculu m treatments(e.g.,antifungaltreatmentofsurfaces,VOCtr eatment ofair)mayoeramorepracticableapproach,buttreatingeveryinfectedNorthAmericanhibernaculuminperpetuityisnotsustainable.Identifyingtheappropriatetreatmentapproac h becomesimportantwhenmonetaryandphysicalfeasibilityistakenintoaccount.Furthermore,dierentbatspeciesmayberespondingtothediseasedierently,understandingthehostresponsewillhelptoprioritizetreatmentofspeciesanddeterminewhetheronetreatmentregimeisappropriateforallspeciesorifindividualtreatmentplansshouldbedeveloped.ImplicationsforAllTreatment-BasedConservationUnderstandingahost'sresponsetoapathogenpriortointerventioniscriticaltosuccess.Whileitistemptingtoa ssume thatanydecreaseinpathogenloadwouldbebenecial,thephysiologyofnaturalimmunitymaynotalwaysallowsuchblack-and-whitesolutions.Aswehaveshown,ifindividualsupregulatephysiologicallycostlyinnateimmuneprotectionsonlyduringpathogenexposureanddownregulatethemoncethethreatispassed,removalofthetriggerforprotectioncancauseaprotectedpopulationtoreverttovulnerability.Inthesecases,treatmentintheabsenceofreasonablebelie f thatthepathogenwillnotbereintroduceduntilafterthepopulationhasrecoveredtopre-infectionsizes(orbeyond)couldbecatastrophic.Ofcourse,thediseaseintheabsenceo f treatmentmayitselfbecatastrophic.Iftheongoingmortali ty issucientlyhightocompromisethelong-termpopulationgrowthrates,treatmentmaybetheonlyoption.Inthiscase,ifinnateimmunityisprovidingprotection,wemustrecognizetherisksofinconsistenttreatmentregimesandcommittoconstanteorts.Thereisstillapointofnoreturnbeyondwhic h evenconstanttreatmentcannotguaranteethepersistenceofthepopulation(e.g.,smallpopulationparadigm,Alleeeects,etc.).Iftheonlymechanismsofprotectionarefromimmunityandnotevolutionaryrescue,treatmentmustbeginearlyeno ugh topreserveasucientnumberofmostlyhealthy,breedingindividuals.Modelsofthissortwillbeacriticaltoolineval uating whenthispoint-of-noreturnmighthappen,whatlevelofecacyisrequiredandwhattreatmentregimewillensuresurvival. Theprospectsforapopulationarebetterundertheprocesses ofevolutionaryrescueevenwithoutintervention.Inthese cases, treatmentbecomesabenecialmechanismforsupportofthepopulationtomitigatetheinitialdropinpopulationsizeasinfectiondecimatesindividualswithoutprotectivegenoty pes. Increasingthesurvivalofunprotectedindividualscanpreve nt thepopulationfromgrowingtoosmall,orbeingmoderatelylowfortoolong.However,treatmentwillalsoeasetheintensity ofthe selectivepressure,slowingtherateofreplacementofunprote cted individualsbyprotectedindividuals.Thesimulationspresen ted hereassumed50%probabilityofprotectionfortheospringofmatingbetweenprotectedandunprotectedindividuals(i.e ., adominanttraitonasinglelocusthatassortsindependently ). Inreality,genetically-derivedprotectionagainstinfect ionis likelyduetoasuiteofgenesthatdonotassortsimply,anddilutionofselectivepressuremustthereforealsobeconsidered. Lastly,evolutionaryrescueisnotmutuallyexclusivewith eitherimmuneprotection,meaningthattheimpactoftreatmen t onreal-worldpopulationpersistencewillentailacomplicatedtrade-obetweenthedilutionofselectiveforces,themiti gationof mortalitycostsfromnewinfectionsduetoongoingtransmis sion, andthepotentialforcompromisingongoinginnateimmuneprotectioninalready-exposedindividuals.Bytailoringmod els toreectthegeneticandimmunologicalprocessesofparticul ar systems,wecanbegintoconsidercertaintreatmentstrategi es, weighingtheseimpactsexplicitly,anddiscoveringhowbestt o managepopulationsunderthreat. TheimplicationsofthesemodelsextendbeyondtheWNS epizootic.Fortheincreasingnumbersofemergingwildlifediseases,suchastherecentlydiscoveredsnakefungaldisea se ( Tetzlaetal.,2015 )orthemultipleetiologicallycomplicated coraldiseases( WeilandRogers,2011;Sutherlandetal.,2016 ), ourstudyunderscorestheimportanceofstudyingthehostresponseconcurrentlytoinvestigatingmechanismsofinfect ion andtransmission.Thefungus Batrachochytriumdendrobatidi has causedworldwidedeclinesinamphibianpopulations,leadingtocoordinatedeortstocontrolpathogenspread,understandmechanismsoftransmissionandinfection,andtreatthedise ase ( Whildeetal.,2017 ).However,eortstotreatinfectionhavebeen largelyunsuccessfulanddierentspecieshavevaryingdegre es ofsusceptibility( Heardetal.,2011;Woodhamsetal.,2012 ). Recentevidenceshowsthatimmunosuppressionofthehostbythepathogenmayplayacriticalroleinitsabilitytoinfectho sts ( Savageetal.,2016 )indicatingthatabetterunderstandingofthe hostresponse(s)willhelptoelucidateasuccessfultreatmen tplan forthisdisease.Formorewell-characterizeddiseases,such as Dermoinoysters( Burgeetal.,2014 )orchronicwastingdisease FrontiersinEcologyandEvolution|www.frontiersin.org 7 April2017|Volume5|Article28

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Masloetal. WhiteNoseSyndromeTreatmentModeling incervids( Williamsetal.,2002 ),wherethehostresponsemay bebetterunderstood,ourstudydemonstratesthenecessity of incorporatingwhatisknownofthehostresponseintoanecien t andeectivetreatmentplan. TheimplicationsofthesemodelsextendbeyondtheWNS epizootic.Fortheincreasingnumbersofemergingwildlifediseases,suchastherecentlydiscoveredsnakefungaldise ase ( Tetzlaetal.,2015 )orthemultipleetiologicallycomplicated coraldiseases( WeilandRogers,2011;Sutherlandetal.,2016 ), ourstudyunderscorestheimportanceofstudyingthehostresponseconcurrentlytoinvestigatingmechanismsofinfec tion andtransmission.Thefungus Batrachochytriumdendrobatidi has causedworldwidedeclinesinamphibianpopulations,leadingtocoordinatedeortstocontrolpathogenspread,understandmechanismsoftransmissionandinfection,andtreatthedis ease ( Whildeetal.,2017 ).However,eortstotreatinfectionhavebeen largelyunsuccessfulanddierentspecieshavevaryingdegre es ofsusceptibility( Heardetal.,2011;Woodhamsetal.,2012 ). Recentevidenceshowsthatimmunosuppressionofthehostbythepathogenmayplayacriticalroleinitsabilitytoinfectho sts ( Savageetal.,2016 )indicatingthatabetterunderstandingofthe hostresponse(s)willhelptoelucidateasuccessfultreatme ntplan forthisdisease.Formorewell-characterizeddiseases,su chas Dermoinoysters( Burgeetal.,2014 )orchronicwastingdisease incervids( Williamsetal.,2002 ),wherethehostresponsemay bebetterunderstood,ourstudydemonstratesthenecessity of incorporatingwhatisknownofthehostresponseintoanecien t andeectivetreatmentplan. CONCLUSIONWildlifediseasetreatmentsthatshowpromiseinthelabstillfacesignicanthurdlesbeforetreatmentscanbeappliedsuccessfullytowildpopulations( Langwigetal.,2015b ).Both treatmentecacyinpathogenremovalandthepercentofthehostpopulationthatcanbetreatedgiveneconomicandlogisticconstraintscontributetothesehurdles.However ,beyond thesedirectconsiderationsofdevelopmentanddeployment,ourresultsclearlydemonstratetheneedtoconsidertheimpactoftreatmentontheongoingdynamicsbetweenhostdefensemechanismsanddiseasedynamicsbeforetreatment-basedinterventionscantrulybeaddedtoourarsenalofconservationtools.AUTHORCONTRIBUTIONSBMandNFconceivedoftheidea,NFperformedthemodeling,andBM,NF,andSGinterpretedtheresultsandwrotethemanuscript.ACKNOWLEDGMENTSWewouldliketothankseveralcolleaguesfordiscussionsrelatingtotreatmentandthismanuscript:WinifredFrick,KateLangwig,JulieLockwood,ChristopherCornelison,SybillAmelon,andBarrieOvertonaswellasthereviewers. 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Dis.Aquat.Org. 98,11–25.doi:10.3354/dao02429 ConictofInterestStatement: Theauthorsdeclarethattheresearchwas conductedintheabsenceofanycommercialornancialrelations hipsthatcould beconstruedasapotentialconictofinterest.Copyright2017Maslo,Gignoux-WolfsohnandFeerman.Thisisan open-access articledistributedunderthetermsoftheCreativeCommons AttributionLicense(CC BY).Theuse,distributionorreproductioninotherforumsis permitted,providedthe originalauthor(s)orlicensorarecreditedandthattheori ginalpublicationinthis journaliscited,inaccordancewithacceptedacademicprac tice.Nouse,distribution orreproductionispermittedwhichdoesnotcomplywiththes eterms. FrontiersinEcologyandEvolution|www.frontiersin.org 9 April2017|Volume5|Article28


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