Preface–EmergingViruses:FromEarly DetectiontoIntervention
GiuseppeIppolitoandGiovanniRezza
Keywords
Inthelastdecades,severalvirusesemerged,after cross-speciespassagefromanimalreservoirsand thenspreadinginhumanpopulations;theEbola virus,twodifferentcoronavirusescausingthe severeacuterespiratorysyndrome(SARS-CoV) andtheMiddle-eastrespiratorysyndrome (MERS-CoV),andtheNipahvirus,are paradigmaticexamplesofbiologicalagents completelynewforhumans,withhighepidemic potential,butalsopronetodisappearincase earlydetectionandinterventionareensured (Morse 1993;FauciandMorens 2012).
Othervirusesexpandedtheirgeographical areaofactivityfromtheoriginalecological nichetonewlandsandcontinents,asrecently demonstratedbythelargeoutbreaksofZikaor Crimean-CongohaemorrhagicfeverinSpain, anddengueinMadeira(Portugal).Several arbovirusesrepresentparadigmaticexamplesof microorganismswhichfoundtheconditionsfor theirspreadinpreviouslyunaffectedareas inhabitedbycompletelysusceptiblepopulations, increasingtheirepidemicpotential.Inthisgroup,
G.Ippolito(*)
NationalInstituteforInfectiousDiseasesLazzaro Spallanzani,Rome,Italy
e-mail: giuseppe.ippolito@inmi.it
wefindseveralagentstransmittedby Aedesspp. mosquitoes,fromdenguetochikungunyaand Zika(McCloskeyetal. 2014).
Vector-bornevirusesarenottheonly emergingagentwhichrepresentathreatfor humanhealth,andotherzoonoticvirusesare increasinglyimpactingontheburdenofdisease atthegloballevel(MorensandFauci 2013).To thisregard,zoonosesaccountfornearly two-thirdsofhumaninfectiousdiseases,inpart duetotheincreasinganthropogenicpressureson theenvironment.Leadingdriversofinfectious diseaseemergenceinhumansfromwildlifeare multipleandcomplex,andbroadandnovel approachesarerequiredtotacklethem.The “OneHealth”approach,forexample,considers thehuman-animal-environmentinterfacewitha singleperspective(IOM 2015).Theaimisto promotesynergiesamongpublichealth,informationandcommunication,humanandanimal health,veterinaryandmedicalapproaches,environmentalandecologicalsciences,mathematical modelingandgeographicinformationsystems,
G.Rezza
DepartmentofInfectiousDiseases,IstitutoSuperioredi Sanita ` ,Rome,Italy
e-mail: giovanni.rezza@iss.it
anthropologicalandbehavioralexpertise(Zumla etal. 2015).
Emergingvirusesrepresentanimportantchallengeforglobalpublichealth,andpromptinterventionisneededinordertoputoutbreaksunder control(McCloskeyetal. 2014).Firstofall, earlydiagnosisoftheagentisextremelyimportanttorapidlyidentifytheviralthreatandtostart theinterventionassoonaspossible(Memish etal. 2014).Tothisend,asyndromicapproach andtheuseofanappropriatecase-definitionmay beusefultohypothesizethenatureofthedisease. However,asdemonstratedwithEbolainthe largeoutbreakoccurredinWestAfricain2014, onlyasmallproportionofcaseshadhemorrhagic manifestations,thusrelyingonbleedingdidnot provideavalidcluetodiagnosis.Laboratory diagnosisismorespecificandrepresentsthe goldstandardforthediagnosisofanemergent virus.However,incertaincontexts,itmaybe difficulttoperformrelativelysophisticatedtests underadverseenvironmentalconditions.Moreover,thelackofprotectiveequipmentandhigh securitylevellaboratoriesisanobstacleto handlingpotentiallyinfectedsamples.Toovercomethisproblem,mobileBSL4labshavebeen extensivelyprovidedbytheinternationalcommunitytoallowEbolavirusinfectiondiagnosis duringtherecentoutbreakofEbolainWest Africa.
Responsecapacity,especiallybyresource poorcountries,andrapidinterventioninthecontextofexplosiveoutbreaksiskeytomitigateor controlepidemicevents(Anemaetal. 2014). WithdiseaseslikeEbola,thataretransmitted throughdirectcontactwithdiseasedpersons, deadbodies,orbodilyfluids,andareamplified bythefamilyandthehospitalsettingorburial ceremonies,avoidingcontactwithphysical barriersisratherefficientandproductive. Measuresastheavailabilityofalargenumber ofhospitalbedstokeepinfectedpatientsaway fromthecommunity,protectiveequipmentand trainingofhealthcareworkerstoavoiddirect contactwithpatientfluids,restrictionof movementstominimizetheriskofintroduction
oftheinfectiontonaı¨veareasarelikelytosucceedwhencomplementedbycorrectinformation,labevidencebaseddecisionmakingfor keepingpatientsunderisolation,highquality careandtreatmentofconfirmedpatients.
Withmosquito-transmitteddiseases,which recentlycausedseverallargeoutbreaksinmany poorresourcecountries,preventionalsoplaya majorrole.Aparadigmaticexampleis representedbythespreadofchikungunyaand ZikainLatinAmericaandCaribbean,where denguewasalreadypresent.However,mosquito controlactivitiesmaybesuccessfulin controllinglocaloutbreaksoccurringintemperateareasbutdonotappearabletomitigatelarge epidemicsintropicalareas.Forthisreason,the availabilityofsafeandeffectivevaccinesis essentialinordertokeepviruscirculationunder control.
Therearenovaccinesavailableagainstmost emerginginfections,andthismaybeexplained byaseriesoffactors.First,fortheirownnature, emerginginfectionshaveoftenepidemicpatterns thatminimizethefeasibilityoflargeefficacy trials,whicharenowconsideredthegoldstandardforvaccineevaluation.Infact,theconductionoflargestudiesislimitedbythe unpredictabilityoflargeoutbreakswhere vaccinesmaybetestedonlargepopulation groups;secondly,forthesamereason,vaccine demandmaybedifficulttoassess;thirdly,limitedresourcesareallocatedtovaccineresearch anddevelopmentwheneconomicreturnisnot ensured.
Forexample,identifyingthetarget populationsforvaccinationcampaignsisnotan easytask.ForEbola,healthcareworkersinhigh riskareasmightbeatarget,aswellashealth professionalswhointerveneincaseofoutbreaks. Finally,ringvaccinationofdirectandindirect contactsofinfectedpatientsmightbevaccinated toreducetheriskofdiseaseandtransmissionin anaffectedarea.
Vaccinesagainstafewarboviraldiseases, suchasthoseagainstyellowfeverandJapanese encephalitis,havebeenextensivelyused.In
particular,theliveattenuatedvaccinesagainst yellowfever,whichwascreatedinthe1930s, hascontributedtothecontrolofthediseaseboth inAfricaandinSouthAmerica.However,a vaccineagainstdengue,whosetargetis representedbythelocalcommunitiesinaffected areaoftheworld,hasproventobeonlypartially effective,andvaccinesagainstchikungunyaand Zikaarestilllacking.
Nevertheless,makingvaccinesandeffective drugstobeusedasprophylaxisincaseofdetectionofearlychainsoftransmissionofemerging viruses,asitmayhappenwithamutatedstrainof avianinfluenza(i.e.,a“humanized”H5N1or H7N9fluvirus)wouldbeveryusefulif complementedbyeffectivemolecularsurveillance(HuiandZumla 2015;Marstonetal. 2014).
Inthisvolume,wepresentaseriesofarticle onmechanismsanddriversofemergenceof novelvirusinfectionsinhumanpopulation, tryingtofocustheattentiononaspectswhich havenotfrequentlyaddressedbefore.
Forthisspecialissue,thearticleswrittenby internationallyrenownedexpertscoverseveral areasofresearch.InthepaperbyBusanietal., theapplicationofthetheoryoffocalityof diseasestoinfectiousdiseaseisdiscussed, providingparadigmaticexamplesofviral diseases(Busanietal. 2016).Theproposed approachisrepresentedbydetailedmappingof theareasofactivityofbiologicalagentscausing naturalfocaldiseasesalongwithevidence-based interventions,suchastargetedvaccination.
InCastruccireview,theHuman-animalinterfaceisdiscussed,withaaspeficicfocuson influenza.Thetopicisparticularlyimportant, since“humanization”ofavianvirusesrepresents apersistentthreattohumanhealth(Donatelli etal. 2016).
IntheSerra-CoboandLo ´ pez-Roigpaper,the rolesplayedbybatsinemerginginfectionsis presentedanddiscussed.Maintenance mechanismsandtransmissionofbatviruses wereanalyzed,takingintoaccountthephylogenetichistory,coevolutionprocesses,batadaptationtoliveindifferentenvironments,and
specificbehaviourofdifferentspecies.These factorsallowtoassesstheepidemiologicalrisk forhumansandtoplanpreventivemeasures (Serra-CoboandLo ´ pez-Roig 2016).
InAzharetal.report,anoverviewofMiddle EastRespiratorySyndromeCoronavirus (MERS-CoV)epidemiologyanditsclinical featuresisprovided.Thepaperhighlightsthe knowledgegapsandtheepidemicriskpotential forglobalspreadofthisemergentcoronavirus (Azharetal. 2016).
ThecurrentZikaviruslargeoutbreakoccurringinPacificOceanandtheAmericas,includingthecriticalaspectforacoordinatedresponse, isdescribedbyBordietal.Severalaspects,such asthemodeoftransmission,therisksassociated withpregnancyininfectedmothers,theassociationoftheviruswithsevereconsequences, includingfetal/newbornmicrocephalyand Guillain-Barre ´ Syndromeinadults,arediscussed inthepaper(Bordietal. 2016).
Animalmodelsareessentialforthestudyof emerginginfections,toimprovediseaseknowledgeandfordevelopingtherapeuticdrugs. Warneretal.describetheuseofsmallanimal modelsforthestudyofinfectiousdiseases,with specialfocusontheSyriangoldenhamsters emergedasanidealanimalmodel,duetotheir lowcost,smallsize,easeofhandling,andability toaccuratelyreflectdiseaseprogressionin humans.Inthepaper,valuableinformationto researcherswhoaredecidingwhethertouse hamstersasananimalmodelisprovided(Warner etal. 2016).
The2014–2015EbolavirusoutbreakinwesternAfricaillustratesthethreatcomingfrom emerginginfectiousdiseasesandisperceived bythepublicasapreeminentglobalhealthproblem.Nicastrietal.presenttheactivitiesandthe challengingissuesencounteredintermsofmedicalmanagementofthepatients,preparedness andresponsetotheoutbreaks,diagnosticand researchchallenges(Nicastrietal. 2016).
Highlyinfectiousdiseasescanspreadrapidly acrossbordersthroughtravelortrade,andinternationalcoordinationisessentialtoapromptand
efficientresponsebybio-containment laboratories.AprioritizationofhighconsequencevirusesisessentialtoimproveEuropean laboratorypreparednessforcross-borderhealth threats.Thestrategytoidentifyprioritiesfora rationalallocationofresourcesforresearchand surveillancehasbeenthefocusofalargebodyof researchinrecentyears.Theactivitiesandthe thestrategyusedbyEMERGE,anEuropeanwideconsortiumfundedbytheEuropeanCommission,aredescribedinthepaperbyNisii etal.(2016).
Newemergingtechnologiesareusefulfor detecting,tracking,reporting,forecasting,and improvingearlywarningsystemsandproper response.Tothisregard,Al-Surimietal. highlightsanddiscussthepotentialroleofsocial mediainpreventingandfightinginfectious diseases,summarizingtheadvantagesand limitationsofsocialmediaandInternet-based dataforpublichealthsurveillance,inorderto identifythegapsthatstillrequirefurtherresearch andimprovement(Al-Surimietal. 2016).
Thepaperspublishedinthisspecialissue presentexciting,insightfulobservationson emergingviralinfections.Inthisrapidlydevelopingfieldofstudy,interdisciplinaryandchallengingresearch,performedinboth industrializedandresource-limitedcountries, canbringcriticallyimportantinformationfor lifeandsocialsciences,forpublichealth,and forhealthcareoverall.Theaimofthisspecial issueistocontributetothedevelopmentof knowledgeonemerginginfectionintheendless warfarebetweenvirusesandman.However,the articlesincludedinthisvolumearenotrepresentativeofthewholefieldofemerginginfections, sincetheyhavebeenselectedwiththeaimof presentingapointofviewonuncoveredissuesor providinginsightsonkey/hottopicsforwhich scientificknowledgeisrapidlyevolvingknowledge.Thus,ourintentionwasnottoconducta systematiccollectionofallemerginginfections, buttoaddressspecificissuesthatmaybeimportantinordertounderstandwhyandwhenanew agentmayemerge,andhowwemayintervenein aneffectiveway.Wehopewesucceeded,atleast inpart,inthisdifficulttask.
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AdvExpMedBiol-AdvancesinMicrobiology,InfectiousDiseasesandPublicHealth(2017)6:7–16
DOI10.1007/5584_2016_199
# SpringerInternationalPublishingSwitzerland2017
Publishedonline:18February2017
HowtoTackleNaturalFocalInfections: FromRiskAssessmenttoVaccination
LucaBusani,AlexanderE.Platonov,OnderErgonul,
andGiovanniRezza
Abstract
Naturalfocaldiseasesarecausedbybiologicalagentsassociatedwith specificlandscapes.Thenaturalfocusofsuchdiseasesisdefinedasany naturalecosystemcontainingthepathogen’spopulationasanessential component.Insuchcontext,theagentcirculatesindependentlyonhuman presence,andhumansmaybecomeaccidentallyinfectedthroughcontact withvectorsorreservoirs.Someviruses(i.e.,tick-borneencephalitisand Congo-Crimeanhemorrhagicfevervirus)areparadigmaticexamplesof naturalfocaldiseases.Whenenvironmentalchanges,increaseofreservoir/vectorpopulations,demographicpressure,and/orchangesinhuman behavioroccur,increasedriskofexposuretothepathogenmayleadto clustersofcasesoreventolargeroutbreaks.Interventionisoftennot highlycost-effective,thusonlyafewexamplesoflarge-scaleoreven targetedvaccinationcampaignsarereportedintheinternationalliterature. Todevelopinterventionmodels,riskassessmentthroughdiseasemapping isanessentialcomponentoftheresponseagainsttheseneglectedthreats andkeytothedesignofpreventionstrategies,especiallywheneffective vaccinesagainstthediseaseareavailable.
Keywords NaturalFocalDiseases•Viruses•TBE•CCHF•Vaccination
L.Busani
DepartmentofVeterinaryandFoodSafety,Istituto SuperiorediSanita ` ,Roma,Italy
A.E.Platonov
CentralResearchInstituteofEpidemiology,Moscow, Russia
O.Ergonul
DepartmentofInfectiousDiseases,Koc¸University, Istanbul,Turkey
G.Rezza(*)
DepartmentofInfectiousDiseases,IstitutoSuperioredi Sanita ` ,VialeReginaElena,299Roma,Italy
e-mail: giovanni.rezza@iss.it
A“naturalfocusofaninfectiousdisease”isa conceptderivingfromthetheoryoffocalityof diseases,proposedbytheRussianscientist EugenePavlovskyin1939.Accordingtothis theory,somepathogensareassociatedwithspecificlandscapes,andthenatural“focus”or “nidus”ofaninfectiousdiseaseisdefinedas “anynaturalecosystemthatcontainsthepopulationofapathogenasanessentialcomponent” (Korenberg 2010).Thedeterminantfeatureof natural-focaldiseasesisthatthepathogen circulatesinnatureindependentlyfromhuman presence.Asarule,humansbeingsbecome infectedwhentheygetintothefocusandhave contactwiththeinfectiousvectoror,insome cases,withthereservoirhost(Korenberg 2010).
Todeveloptheconceptofnaturalfocality, Pavlovsky,inhisoriginaltheory,analysedtickbornepathogensinRussia,andforsuch pathogenshestatedthatthefocusofinfection shouldhavethreecriticalelements:
1.Theaetiologicalagentofthedisease; 2.vertebratehostsplayingdifferentroles(infectiousandsusceptiblerecipienthosts, reservoirs);
3.environmentalfactorsenablingthecirculation andpersistenceoftheagent.
Startingfromthisoriginalformulationrelated tovector-bornediseases,thedefinitionofnatural focalitywasappliedalsotonon-vector-borne zoonoses,suchashemorrhagicfeverwithrenal syndrome,Ebola(whenrestrictedtoitsnatural nїche),leptospirosis,andotherinfectious diseases.Finally,naturalfocalityforalarge groupofsapronoticinfections,whoseagents liveinsoiloraquaticecosystems,wasalso describedanddiscussed.Forsomevector-borne zoonoses,theconceptofafocus(nidus)maybe implementedaswell.Thus,thephenomenonof naturalfocalityiswidespread,andincludesmany natural-focaldiseaseswithdifferenttypesof transmission.
Thenaturaltransmissionofapathogen,inthe contextofnaturalfocality,shouldbeconsidered a“continuousinteractionofthepathogenpopulationwiththepopulationsofitsnaturalhosts
andtheenvironment,whichprovidesforthe existenceofthepathogen”(Korenberg 2010). Suchprocessisaseriesofconsecutivecyclesof pathogenreservation(restriction)andspread (circulation),providingtheprocesstobelimited intimeandspacebythepresenceofspecific conditionsneededbythepathogen.Moreover, thecirculationofthepathogeninthenatural fociisindependentonhumanpresence,and humaninfection,withrareexceptions,isa “biologicaldeadend”forthepathogen.The interactionbetweenpathogensandhumansisan accidentaleventanddoesnothaveanycoevolutionaryconsequence(WHO 2016).Anoutbreak directlyconnectedwithnaturalfociisactually thesumofindividualdiseasecasesoccurringin differentplacesindependentlyoneachother, withinfectionoftenbeingacquiredfromoneor severalsourcesnotconnectedwithotherdiseasedpersons(Korenberg 2010).Thisconcept isimportanttodistinguishzoonoseswithnatural focalityandhumaninfectionsacquiredfrom domesticanimals.Anotherdifferencebetween naturalfocaldiseasesandotherzoonosesisthe relevanceofthesocio-ecosystemlevelinthe structureoftheepidemicprocess,whichmaybe highforseveralzoonoticinfectionsbutusually doesnotplayanyroleincaseofzoonoseswith naturalfocality.
However,itshouldbetakenintoaccountthat biologicalandsocialfactors,andincreasingly intensivehumanactivities,cancausedrastic changesinthestructureandfunctioningofparasiticsystems,thefrequencyandformsofhuman contactwithnaturalfoci,andeventhepathway ofpathogentransmissiontohumans.
This“basal”interpretationoftheepidemic processininfectionswithnaturalfocality remainsunchanged.Itshouldonlybetakeninto accountthatpeoplethemselvescreateconditions fortheirexposure,favouringtheentranceof pathogensfromnaturalecosystemsintotheir immediateenvironment,andfortheiractive reproductionandamplificationinthisnewenvironment.Forexample,epidemicoutbreaksof hemorrhagicfeverwithrenalsyndrome,atypical zoonosiswithnaturalfocality,areusually associatedwithvirussheddingbyanimal
reservoirs(murinerodents)migratingto populatedareas,wherefavourableconditions forvirusamplificationarecreatedwhenthe abundanceoftheseanimalsreacheshighvalues (Korenberg 2010).
Inthepasttwodecades,viewsonthediversity,spread,andepidemicsignificanceof infectionswithnaturalfocalityhavechanged substantiallyallovertheworld.Somenew pathogenshavebeendiscovered,andperiodic epidemicmanifestationsofnaturalfocihave becomeamatterofgreatconcern.Moreover, increasinghumanactivity(e.g.,intensivesuburbanconstructionaroundbigcities,expansionand growthofrecreationalpressure)haveledtoa significantincreaseincontactbetweenhuman populationsandnaturalfoci,creatingfavourable epidemiologicalconditionsforthespreadof natural-focaldiseases(Malkhazovaetal. 2014). ThelargeoutbreakofEbolaoccurredinWest AfricafromDecember2013toMarch2016, affectingthreecountries(Guinea,Liberia,and SierraLeone),isanexampleoftheepidemic potentialofnaturalfocaldiseasesifvirus properties(capacityofinter-humantransmission),environmentalfactors,andsocial conditionsconcurtoincreasetheforceofinfection,leadingtolarge-scaleviruscirculation throughouthumancommunities.Attheendof theoutbreak,morethan28,000casesand11,000 deathswerereported(WHO http://www.who.int/ csr/disease/ebola/en/).
1Eco-Epidemiology:How toPredictandControl theOccurrenceofNatural FocalInfectiousDiseases
Currentunderstandingabouttheglobaldistributionofmostinfectiousdiseasesissurprisingly limited.Inparticular,thespatialdistributionof thevastmajorityofnaturalfocaldiseases remainslargelyunknownandmanyquestions arestillunsolved,mainlybecauseofthepoor knowledgeoftheirlocalvariationsandofthe characteristicsoftheecologicalnichesthat allowthepermanenceofsuchdiseasesintheir naturalenvironment.Duetotheirintrinsic features,thetransmissionoffocaldiseasesto humansishighlyheterogeneousinspaceand time.Atthemicro-epidemiologicalscale,numerousfactorsinfluencethetransmissiondynamics ofthediseasesinendemicfoci,andvariationsin thedistributionofthesefactors,eveninasmall area,canresultinspatiallyheterogeneoustransmissionandappearanceofdiseasehotspots, wheretransmissionintensityishigherthanin thesurroundingareas.
Thereareseveralreasonsformappingthe geographicaldistributionofinfectiousdiseases. Mapsofdiseasedistributionandintensityallow animmediatevisualizationoftheextentand magnitudeofthepublichealthproblem.These mapscanalsodocumentthebackgroundlevelof thediseaseinordertomonitoritstrendandto evaluateinterventions.Anotherreasonisthat mapsmayalsoprovideinformationonthe factorsthatfavourtheemergenceofinfectious diseases.
Natural-focaldiseasepreventionisoneofthe mostchallengingpublichealthproblems.Agents andvectorsofthesediseasesarepartofnatural landscapesandthespreadofthesediseases, whichmayrepresentaserioushazardforpeople, isdeterminedbynaturalfactors.Suchfactorscan beidentifiedanddescribedintheaffectedarea,in ordertoidentifythe“hotspots”ofthedisease, whicharethemostsuitableplacesfortheagents andvectors.Asproxyofthelandscapefeatures, alsohistoricaldataonbiocenosis,healthrecords ofhumansandothervertebratehosts(domestic andwildanimals)canbeused.Withsuchinformation,predictionsontheprobabilitythata givenbiologicalagentispresentinaspecific areaarepossible.Moreover,thisinformation canbeplotted,tryingtoidentifythegeographical distributionofthenaturalfociofinfectionina givenarea.Therefore,medicalgeographyhasan importanttask:evaluatingtheriskofepidemic hazardsofnaturalecosystemsandproviding publichealthauthoritieswithrecommendations necessarytopreventdiseaseoutbreaksandconductepidemiologicalsurveillance.
Herebywepresentsomeinnovative approachestodiseasemappingwhichprovide usefulinformationandpredictions.
1.1EcologicalNicheModelling
Awiderangeofapproacheshasbeendeveloped forempiricalmodellingofspeciesanddisease distributions,makinguseofdataonpoint observationsofdiseaseoccurrence,withthe objectiveofidentifyingthefundamentalniche ofthetargetorganism(Hayetal. 2013).Some oftheseapproachesallowtoaccountforenvironmentalcovariates,dataonpresenceofpathogens andnaturalhosts,landscapes,andclimate information.
Theconceptofecologicnichewasproposed byJosephGrinnell(1917)whowasthefirstto exploreconnectionsbetweenecologicalniches andgeographicdistributionsofspecies. Accordingtohisproposal,theecologicnicheof aspeciesisthesetofconditionsunderwhich speciespopulationsmaybemaintainedwithout immigrationofindividualsfromotherareas.The ideabehindnichemodellingisthatknown occurrencesofspeciesacrosslandscapescanbe relatedtorastergeographicinformationsystem coveragessummarizingenvironmental variationsacrossthoselandscapes,toestimate theecologicalnicheofthespecies(Peterson etal. 2002).Suchamodellingapproachcanbe usedtoidentifypotentialdistributionalareasfor speciesonanylandscape,whichmayinclude unsampledorunstudiedportionsofthenative landscape(Lo ´ pez-Ca ´ rdenasetal. 2005),areas ofactualorpotentialinvasionbyspecieswith expandingranges(TownsendPetersonandKluza 2003),orchangingpotentialdistributionalareas asaconsequenceofchange(e.g.,landuse changeorclimatechange)(Escobaretal. 2015).
Ecologicalnichemodelling,maybeusedto characterizedistributionalareasofspeciesin complex,linkedgeographicandecologicspaces. Itpermitsresearcherstocharacterizeecological needsofspecies,interpolatebetweensampling pointstopredictfulldistributionsofspecies, predictspeciesdistributionintobroadly
unsampledareas,predictinvasivepotentialin otherregions/continents,predictlikelydistributionalchangewithchanginglanduse,predict likelydistributionalchangewithchanging climates,andbuildscenariosforunderstanding andcharacterizingunknowndiseasebehaviour. Hence,ecologicalnichemodellingoffersapowerfultoolforcharacterizingecologicandgeographicdistributionsofspeciesacrossrealworldlandscapes(Peterson 2008a, b).
1.2TheBoostedRegressionTrees Method
Tomaptheoccurrenceofagivendisease,the boostedregressiontreesmethod(Elithetal. 2008;De’ath 2007)isoneofthemostperforming methods;itisflexibleinbeingabletoaccommodatedifferenttypesofpredictorvariables (e.g.continuousorcategoricaldata)andeasyto understand,implementandusesreliable.The mapsgeneratedwithsuchapproacharesimple tointerpretandincludearankedlistofenvironmentalpredictors.
Anotherapproachthathasrecentlybeenmore widelyappliedininfectiousdiseasemappingis themodel-basedgeostatistics(Diggleand Ribeiro 2010)thathasimportantadvantages whencomparedtotheboostedregressiontrees method:(i)itdealsexplicitlywiththespatial (andwithextensiontemporal)autocorrelation ofdiseasedata.Thisisstillwidelyignoredin occurrencemapping;(ii)itoffersamuchmore robustparameterizationoffactorsthatcanaffect diseaseendemicity(suchasageofthe individualssampled,thediagnostictechnique used,theinfluenceofcovariatesetc.);(iii) outputscanalsoshowthefulluncertaintyofthe predictioninallpartsofthepredictedmapsby fittingthemodelsusingBayesianinference.
1.3Macroecology
The“macroecology”appearstoprovideanew perspectiveinidentifyingdriversofinfectious diseasepatternsandimpactsatthebroadest
scalesoforganisation.Macroecology investigatespatternsandprocessesatbroadspatial,temporalandtaxonomicscales,expanding scientificunderstandingofglobalinfectiousdiseaseecology.Inparticular,itcouldhelp providingnewinsightsaboutscalingproperties acrossalllivingtaxa,andnewstrategiesfor mappingpathogenbiodiversityandinfection risk.Macroecologyseemsausefulframework tomoreaccuratelypredictglobalpatternsof infectiousdiseasedistributionandemergence (Stephensetal. 2016).Researchintherelatively newdisciplineofmacroecologycoversimportantfindingsandadvancesincomputationaland statisticalmethodsexplaininghow macroecologicalapproachescaninformhuman healthandconservationinitiatives.The advancedcomputationaltechniquesareapplied toenormousdatasetstolookforpatterns;inthe caseofdiseaseecology,thiskindofanalysiscan helpscientistsunderstandrelationshipsamong parasites,hostsandtheirenvironments.
Indeed,thedevelopmentoftheprinciplesand methodsofsynthesizinginformationfromdifferentsources,includinggeography,toobtainnew knowledgeaboutthespatialdistributionpatterns ofnatural-focaldiseasesusingnewapproachesis aresearchinterest.Thescientificandmethodologicalbasisofdiseasemapping,usinginformationonlandscapeandenvironment, mathematicalmethods,andmultivariableanalysis,iswelldevelopedandundercontinuous improvement;however,practicalexperienceare extremelylimitedinmappingdiseasesata broaderlevel(nation,area,continent).
Theabilitytomapadiseasestemslargely fromthetypeandqualityofdatathatareavailableformapping.Theaccuracyofmapsisthen largelydeterminedbytheabundance,spatialrepresentativenessandheterogeneityofthosedata (Hayetal. 2013).
Differencesinqualityandincompletenessof initialinformationmakeitdifficulttoobtaina completepictureofthedistributionofnaturalfocaldiseaseswithinaterritory.Inparticular, detailsondisease/pathogenpresenceorabsence inagivenareaislimited,duetothelimitationof thesurveillanceactivityinhumans,domestic
animalsandwildlife,andthefewecological studiesondiseaseswithnaturalfocality (Malkhazovaetal. 2014).
Theknowledgeofhumandistributioninmany areasoftheWorldremainsalsosurprisingly poor.Formanylowincomecountriesofthe World,spatiallydetailed,contemporarycensus datadonotexist.Thisisespeciallytrueformuch ofAfrica,wherecurrentlyavailablecensusdata areoveradecadeold,andatadministrative boundarylevelsjustbelownational-level(Hay etal. 2005;Tatemetal. 2008).Thisinformation isofsignificantimportanceforderiving populationsatriskandinfectionmovement estimates.
Anotherkeyfactorthatmayaffectthedistributionandthepredictionofnaturalfocal diseases,togetherwithalargenumberofother humanandanimaldiseases,isclimatechange. Species’responsetoclimatechangearevariable anddiverse,yetourunderstandingofhowdifferentresponses(e.g.physiological,behavioural, demographic)relateandhowtheyaffectrelevant populationparameters(e.g.populationpersistence)islacking.Muchoftheresearchon responsestoclimatechangedoesnotconsider howpopulationsize,populationgrowthrate,or extinctionriskvariesasafunctionofclimate; consequently,themechanismscausingclimateinducedpopulationchangesarestillpoorly understood(vandePoletal. 2010).Suchlack ofknowledgeimpactsonthecapabilitytomake consistentpredictionsofthepopulationdynamicsofbothhostsandrelatedpathogens.
2NaturalFocalDiseases MappingandControl:Two ParadigmaticExamples
Detectionofthehotspotsofnaturalfocal diseasesthroughthedifferentmapping approachesisakeyactiontobettertargetcontrol effortsandtoreduce/stopinfectiontransmission inthoseareaswheretransmissionintensityis higherforseveralreasons.Theidentificationof areasandhumanpopulationsatriskisessential forbetteraddressvaccinationcampaignsand
otherinterventions.However,onlyfewnatural focaldiseaseshavebeenstudiedindetail mappingtheirfoci,andvaccinesareavailable forfewofthem.Herebywereportavailable informationfortwoimportantnaturalfocal viraldiseases.
2.1Crimean-CongoHemorrhagic Fever:AMappingExercise
Crimean-Congohemorrhagicfever(CCHF)isa tickbornediseasecharacterizedbyfeverand hemorrhagicmanifestations,withfatalityrates upto30%.Thediseasewasinitiallydescribed byRussianscientistsinthe‘40s,whilethevirus wasisolatedthefirsttimeintheDemocratic RepublicofCongosomeyearslater.CCHF virus(CCHFV)circulationhasbeenreported throughoutbroadregionsofAfrica,Europe,the MiddleEast,andAsia,withageographicdistributionoverlappingthatofthe Hyalomma tick, themainvectorsofCCHFV.CCHFVisoneof themostgeographicallywidespreadtick-borne pathogensofmedicalimportanceandmayspread tonewareasifglobalizationandclimatechanges createnewopportunitiesforvirusintroduction andamplificationinsuitableecologicalniches (Hewson 2007)(Papaetal. 2015).
CCHFisconsideredadiseasewithnatural focality,sincetheCCHFVismaintainedin activefocithroughacomplexcyclethatinvolves ixodidticks,mainlyofthegenus Hyalomma (theroleinnatureofothertickspeciesinthe naturaltransmissionormaintenanceofCCHFV isnotclearlydemonstrated)andreservoirhosts (e.g.wildanddomesticungulates,domesticlivestock),onwhichadultticksfeed.Alsoother mammals(rodents,pets)andbirdscanplaya roleinthespreadandmaintenanceofthevirus transmissioncycle.
Littleisknownabouttheinfectionratesin bothvectorsandhostsinnature.In Hyalomma ticks,prevalenceofinfectionisestimatedtobe about5%,butlargegeographicalvariability exists,duetolocalenvironmentalconditions, andtopresenceandabundanceofthedifferent typesofhosts.
Inmammalhosts,theprevalenceofinfection ispoorlyinvestigated,especiallyinwildlife. Domesticruminantsplayacrucialroleinthe lifecycleofthevectorticksandthetransmission andamplificationofthevirus.Inmostlivestock speciesviremiacanlastsupto14days,thus immuneresponsestarts,andtheantibodyprevalenceinthoseanimalsisagoodindicatorforthe presenceofCCHFVinaregion.Recentstudies conductedindifferentregionsofBulgariaand Turkeyshowedanoverallprevalenceindomesticruminantsbetween26and57%,butinsome areastheprevalencewasupto90%(Mertens etal. 2016).Thepotentialusefulnessofsmall ruminantsasindicatoranimalstodeterminethe presenceorabsenceofCCHFVinagivenregion isalsohighlightedbySchusteretal.(2016),who pointedoutalsothelimitedknowledgeaboutthe mechanismsgoverningthedynamicsofCCHFV circulationinasuitablehabitatandtheroleofthe variousanimals.Suchcirculationislinked variableslikeageoftheanimals,with dimostrationofincreasingantibodyprevalence byincreasingageofthetestedanimalpopulation (Wilsonetal. 1990;Bartheletal. 2014)husbandryconditions,usageofrepellents,hostpreferencesoftheticksandsusceptibilityofanimalspeciesandbreedsforCCHFV.
Largeungulatesandlivestockareusually asymptomaticandonlyactivetestingcanshow infectioninthesespecies.Becausethelackof symptomsinanimalsandtheshortlife-cycleof Hyalomma ticks,withoutactivevirologicaland serologicalsurveillanceinanimalsandticksitis unlikelytodetectinfectioninanimalsearlier thaninhumans.Thus,thedetectionofhuman casesisoftenthefirstsignofCCHFVcirculation inanarea.
MappingofthehumancasesisawaytorepresenttheCCHFdistribution.TheWorldHealth Organization(WHO)producedmapsofthediseaseatglobalscale,(http://www.who.int/csr/dis ease/crimean_congoHF/Global_CCHFRisk_ 20080918.png?ua¼1),butthismaprepresents merelythereportedoccurrenceofhumandisease ratherthanthedistributionofthevirus.Thisis duetothecharacteristicofthesurveillance (capacitytodetecthumancasesindifferent
countries/areas,underreporting,underdiagnosis); thedisease(avariablebutrelevantproportionof casesaresubclinical,andthisproportionmay varyindifferentgeographicalareas);specific localconditions,likeinSpain,whereviruscirculationwasdetectedintickssince2010,butno humancaseswereobserveduntilthesummerof 2016(Estrada-Pen ˜ aetal. 2012;Garcı´aRada 2016).
Anewperspectiveontheuseofoccurrence data,whichwasfirstlydevelopedfordengueby Bhattetal.(2013),hasbeenthenappliedto CCHFbyMessinaetal.(2015).Thisapproach isbasedonthecreationofalargedatabaseby assemblingcontemporarydataonCCHFoccurrencetogetherwithgeographicallocationanda suiteofenvironmentalcovariates.Suchdata havebeencollectedfrommanydifferentsources ofinformation,includingthereportingofofficial surveillancesystems,thescientificandtechnical literatureandinformalonlineresources.New modellingapproachesarethenappliedtothe largedatasettomaximisethepredictivepower ofoccurrencedata.Asaresult,highresolution spatialmapoftheprobabilityofoccurrenceof humanCCHFinfectioncanbederivedatglobal level(Messinaetal. 2015).
Anexampleofsuccessfulmodellingapproach isthepredictionofCCHFexpansioninWestern PalearcticmadebyEstrada-Penaetal.They developedadynamicmodelforCCHFVtransmissioninwesternPalearcticthatconsideredthe tickvector, Hyalommamarginatum andthe effectsofvariationsintemperatureandwater vapouronhteticksurvival(Estrada-Pen ˜ aetal. 2013).Themainoutcomewasthatincreaseof thetemperatureiscompatiblewiththespreadof CCHFVinthewesternPalearctic,because expansionofthehabitatsuitablefortickvectors. Accordingtothisscenario,increasedviruscirculationwouldhappeninsiteswherehightick populationsmayalreadyexist.Thisscenario wasconfirmedbytheoccurrenceofahuman caseinSpainin2016(Garcı´aRada 2016).
Combinationofsurveillanceinhumans,host animals,andvectorsismuchmoreinformative ofthedistributionofthevirusandtheareasat riskofhumanexposure;however,itisrarely
carriedoutduetothecostsandthedifficulties toestablishreliablesurveillanceactivityin animals,especiallyinwildlife.Serological surveysinlivestockhavebeenconductedindifferentcountries,providingsnapshotsofthecirculationofthevirusindomesticanimals(Adam etal. 2013;Lotfollahzadehetal. 2011).
Surveysintickshavealsobeencarriedoutto identifyareaswithpotentialviruscirculation. Recentexperienceofsystematicticksurveillance demonstratedtherecentcolonizationofthecontinentalFranceby H.marginatum;thisregion wasconsideredfreefromthetick(Vialetal. 2016).
InEurope,ticksarethemostimportant vectorsofhumanandanimalinfectiousdiseases, andtransmitmorepathogensthananyother arthropod(JongejanandUilenberg 2004; Colwelletal. 2011).Monitoringofticksrequires integratedapproach,withexpertiseinenvironmentalscienceandentomologyasacomplement tothehumanandanimalhealthcompetencies.
2.2AVaccineforCCHF:Give PreventionaChance
InitialattemptstodevelopCCHFvaccinesgoes backtothe1960s,whenSovietscientists advocatedtheimmunizationoflocalpopulations inendemicareas.In1974,theSovietvaccine waslicensedinBulgaria.Thisinactivatedvirus vaccineisthecurrentlyonlyavailableCCHFV vaccine,howeveritsclinicalefficacywasnot clearlydemonstrated(Mousavi-Jazietal. 2012). Moremodernapproaches,suchasDNA vaccines,recombinantviralprotein-based vaccines,andvirus-likeparticlevaccines,are underdevelopment.Thelackofsuitableanimal modelsinthepasthashamperedthedevelopmentofnew,preventive,andtherapeutic measures.Inarecentstudy,IFNAR-/-micewas foundtobehighlysusceptibletotheTurkeyKelkit06strainofCCHFV.Immunizationwith thecellculturebasedvaccineelicitedasignificantlevelofprotectionagainsthighdosechallenge(1000PPFU)withahomologousCCHFV inIFNAR-/-mice(Canakogluetal. 2015).The
BulgarianvaccinewasusedinCCHFV-endemic areasofthecountryformilitarypersonneland medicalandagriculturalworkersover16years ofage.Noneofthevaccinatedmilitarypersonnel hascontractedCCHF,andnoneofthevaccinated laboratorypersonnelworkingwithCCHFV becameinfectedevenafteroccasionalexposures byneedle(Keshtkar-Jahromietal. 2011).However,detailedinformationonvaccination strategiesadoptedtoreducedtheburdenofdiseaseinendemicfociandtheirpossibleoutcome arenotavailable.Theavailabilityofothereffectiveandsafevaccineswouldrepresentagreat opportunityandneedstobeconsideredinpreparednessplansandcontrolstrategies,along withpublicinformationandbehavioral prevention.
2.3TickBorneEncephalitis:Vaccine UsetoControlaNaturalFocal Disease
Tick-bornediseases(TBDs)areamongthemost rapidlyexpandinginfectionsworldwide.Many newhumantick-bornepathogensarediscovered andseveralnovelTBDsarerecognized.IncreasingburdenofTBDsshowsthatcurrentavailable publichealthinterventionsandapproachesare noteffectiveenough.Vaccinationcouldbea highlycost-effectiveinterventionforpreventing TBDs(S ˇ mitandPostma 2016).AmongTBDsfor whichvaccinesarecurrentlyavailable,tickborneencephalitis(TBE)isoneofthemost widespreadinEurope.TBEcanaffectthecentral nervoussystem,whichmayresultinlong-term/ permanentneurologicalsequelaeorevendeath (Dumpisetal. 1999).AttheEuropeanlevel,TBE presentsanincreasingpublichealthconcernwith vaccinationagainstTBElesswidelyusedthan possibletoreducethediseaseburden(S ˇ mitand Postma 2016).TBEincidenceshowsstrong annualvariationsaswellaslongfluctuations overtimeinaffectedcountries,andanoverall upsurgehasbeenreportedincertainpartsof Europe.Thesechangeshavebeenrelatedtoclimatic,ecological,environmentalandsocioeconomicfactorsthatcanleadtoanincreasedriskof
humanexposuretoinfectedticks.Inaddition, however,theestablishmentofnewnaturalfoci ofTBEviruscirculationhasbeendescribedin areaspreviouslyconsideredfreeofTBE.In Europe,AustriahadthehighestrecordedmorbidityforTBE,withseveralhundred hospitalizedpatientsperyearandseveraldeaths (Kunz 2003).AvaccineagainstTBEbecame commerciallyavailablein1976andwas administeredtothoseathigherrisk(e.g.,people handlingtheinfectiousvirusinthelaboratory andprofessionalpeopleworkinginforestsin highlyendemicregions).Followingtheevidence ofalimitedimpactofvaccinationofatrisk groupsonly,massvaccinationcampaign organizedbytheAustrianHealthauthorities beganin1981.Thevaccinationcoverageofthe Austrianpopulationincreasedfrom6%in1980 to82%in2013andhasexceeded90%insomeof thehigh-riskareas.Theincreasingvaccination coverageledtoasteadydeclineinthenumberof TBEcases,thataretentimeslessthanthe1976, inaddition,between2000and2011,anestimate of4000hospitalizedTBEcaseswereprevented byvaccination(HeinzandKunz 2004;Heinz etal. 2013).Theseresultshavebeenachieved thankstothehighawarenessamongtheAustrian populationandthelargeuseofaneffectiveand well-toleratedvaccine(Kunz 2002).However,it couldbechallengingtomaintainahighvaccinationcoverageinthefuture.Moreover, recommendationstopeoplevisitingaffected areasshouldbedelivered,sincepathogensand vectorsarestillthere.
3Conclusions
Theimportanceofnaturalfocaldiseaseshas beenlargelyneglectedforalongtime.However, theexpansionoffocicharacterizedbyintense viralactivity,eveninpreviouslyfreeareas,has raisedtheattentiononthisthreat.Viraldiseases likeCCHFandTBE,initiallyrestrictedinto smallgeographicalniches,havenowanimportantimpactonhumanhealthinseveralareasof theworld.Insomecases,althoughitmayappear paradoxical,massvaccinationcampaignshave
beensuccessfullyusedtopreventandcontrol focaldiseases.However,mappingtheareasof activityofbiologicalagentscausingnaturalfocal diseases,andassessingthepopulationeffectof interventions,especiallyvaccines,isthebest strategytobetteraddressinterventionsagainst theseemerginginfections.
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AdvExpMedBiol-AdvancesinMicrobiology,InfectiousDiseasesandPublicHealth(2017)6:17–33
DOI10.1007/5584_2016_136
# SpringerInternationalPublishingSwitzerland2016
Publishedonline:28September2016
1Introduction
InfluenzaAvirusesareofmajorconcerntoboth veterinaryandhumanpublichealthbecausethey continuetoemergeandcausehighmortalityin domesticpoultryandrepresentanongoingthreat tohumanhealth.Withtherecognitionthat aquaticbirdsarethemajorreservoirofinfluenza virusesthatsporadicallytransmittodomestic poultry,swine,andhumans,thereisacceptance ofthe“oneworld”conceptofinfluenza(Jernigan andCox 2013).WheninfluenzaAvirusesspread fromtheaquaticbirdreservoirtodomesticpoultry,pigs,andpeople,theycanevolveintoviruses thatcausemildorcatastrophicdiseases.For influenzavirusestospreadfromtheaquaticbird reservoirtohumans,theymustevolvefrom intestinaltropisminwildaquaticbirdswitha bodytemperatureof42 Ctorespiratorytract tropisminhumanswithabodytemperatureof 37 C.Additionally,thevirusmustchangeits receptorspecificityonthehemagglutinin (HA)fromabindingpreferenceforsialicacid (SA)-α2,3inwildbirdstoSA-α2,6inhumans (Klenketal. 2013).Therefore,multiplegenetic changesarerequired.TheRNAgenomeofinfluenzahasahighmutationrate,noproofreading mechanism,andissegmented,whichenablesthe virustobehighlyvariable,continuallyacquire mutations,andfrequentlyreassort.Agricultural practicesthatinadvertentlyfacilitatethe exchangeofinfluenzaAvirusesatthewild bird–domesticbirdinterfaceandatthedomestic bird–mammalianinterfacehavebeenadoptedas theneedtoprovideadditionalanimalproteinto anincreasinghumanpopulationhasgrown.
Hereweconsiderourbasicknowledgeofthe propertiesofinfluenzaAvirusesthatpermit themtobesovariableandthemolecular determinantsofhostrangeandpathogenicity involvedinthegenesisofpandemicinfluenza virusesofdomesticpoultry,pigs,andhumans. Sincethemid-1990s,thenumberofinfluenza threatstobothveterinaryandhumanpublic healthhasincreased,includingthegenesisof triple-reassortantvirusesthatcontaingene segmentsfromwildaquaticbirds,swine,and humans.TheseincludeapandemicH1N1
influenzavirusin2009thatspreadgloballyto humansandtheH5N1andH7N9influenza virusesthatcontinuetoevolveandspread. AlthoughneithertheH5N1northeH7N9viruses havetransmittedconsistentlyamonghumans,the pandemicpotentialofthesevirusescannotbe overemphasized.Ourchallengeistouseour fundamentalknowledgeofinfluenzaAviruses topreventand/orcontroltheemergenceofinfluenzavirusesattheaquaticbird–domesticbird–mammalianinterface.
2TheViruses
Influenzavirusesareenveloped,negative-sense, single-strandedRNAvirusesofthefamily Orthomyxoviridae,andtheyexistas3different types:A,B,andC.InfluenzaAandBvirusesare associatedwithseasonalepidemicsinhumans, andinfluenzaCvirusesgenerallycausesporadic infections.OnlyinfluenzaAvirusesarefoundin anumberofmammalianandbirdspecies (Wrightetal. 2007;Websteretal. 1992),and theyarefurtherclassifiedintosubtypesbasedon theantigenicpropertiesoftheirspike-likesurfaceglycoproteins,HAandneuraminidase(NA). Atpresent,18HAsubtypes(H1–H18)and 11NAsubtypes(N1–N11)havebeenidentified. Eachviruscontains1HAand1NAsubtype,and mostoftheinfluenzaAsubtypescanbefoundin numerouspossiblecombinationsinaquaticbird populations,exceptH17,H18,N10,andN11, whichhavebeenfoundonlyinbats(Tong etal. 2012, 2013).Inparticular,wildwaterfowl areconsideredthemainnaturalreservoirfor influenzaAviruses;thus,theyplayacentral roleininfluenzaAvirusecology(Fig. 1).Conversely,onlyafewinfluenzasubtypeshave becomeestablishedinmammals,andH1,H2, andH3aretheonlyonesthathavecausedepidemicandpandemicinfluenzainhumans.
ThegenomeofinfluenzaAvirusisapproximately13.6kbandconsistsof8RNAsegments thatencodeatleast10proteins,thoughafewother proteinshavebeenrecentlydescribedwithas-yet unknownfunctions(PaleseandShaw 2007; MedinaandGarcia-Sastre 2011).Viralparticles
Human–AnimalInterface:TheCaseforInfluenzaInterspeciesTransmission19
Fig.1 SchematicillustrationofinfluenzaAviruscrossspeciestransmission. Solidblacklines indicateinterspeciestransmissionevents.The circle includesthewild aquaticbirdsthatarethenaturalreservoirofmostinfluenza
possessahostcell–derivedlipidenvelope,which containstransmembraneglycoproteinsHAand NAandmatrixproteins(M1andM2)and surroundsthe8ribonucleoprotein(RNP) complexes.EachRNPcomplexcontainsasingle RNAsegmentencapsulatedbythenucleoprotein (NP)andthe3polymeraseproteins(PB1,PB2, andPA)(Arranzetal. 2012;Nodaetal. 2006). HA,whichisresponsibleforvirusattachmentto thehostcell,andNA,whichassistsvirusmaturationandreleasebyactingasasialidase,arethe majortargetsofthehumoralimmuneresponse (Wrightetal. 2007).
InfluenzaAvirusesarecontinuously evolving,and2keymechanismscontributeto theirvariability:antigenicdriftandantigenic shift.Antigenicdriftistheaccumulationof mutationsresultingfromtheinfidelityofthe virus-encodedpolymerase;thus,geneticvariants withselectiveadvantagestoescapethehost’s immuneresponseresult(Fergusonetal. 2003).
Aviruses.The boxes indicatethespeciesmostlikely involvedintheemergenceofzoonoticviruseswithpandemicpotential.Influenzaviruseshavebeenisolatedfrom batsbuttheirroleininterspeciestransmissionisnotknown
Recurrentannualinfluenzaepidemicsinhumans aretheconsequenceofthisgradual,progressive antigenicvariation.Antigenicshiftinvolves majorantigenicchangesbyintroducinganovel HAand/orNAsubtypeintotheimmunologically naıvehumanpopulation,whichleadstoapandemic.Thiseventiscausedbyreassortment, typicallybetweenhumanandavianvirusesin anintermediatehostorbydirecttransmission ofavianorswineinfluenzavirusestohumans (MedinaandGarcia-Sastre 2011;Horimotoand Kawaoka 2005)(Fig. 1).
3MolecularDeterminants ofHost-RangeRestriction andPathogenesis
InfluenzaAvirusesdisplayhost-rangespecificity;however,virusesfromthewildbirdreservoir sporadicallyinfecthumans.Forthistooccur,
Poultry
Dogs
Horses
Aquatic mammals
Aquatic birds
Humans
Cats
Pigs
reassortmenteventsorevolutionaryadaptation ofviralmoleculardeterminantsinanintermediatehostareneededforthevirustoacquire mutationsthatallowitstransmissiontohumans. Ifthishappens,zoonoticdiseasescanoccur throughdirectcontactwithinfectedanimals,as frequentlydescribedforH5,H7,andH9viruses (HorimotoandKawaoka 2005;Kuiken etal. 2006).Nonetheless,zoonoticinfluenza virusesusuallycauseself-limitingillnessin humans,andadditionalmutationsarerequired forthemtobecometransmissiblebetween mammalsviarespiratorydroplets(Neumann andKawaoka 2015;deGraafandFouchier 2014).Althoughitisarareevent,whenthis happens,worldwidespreadandintroductionof anovelvirusintothenaıvehumanpopulation willcauseapandemic.Majordeterminantsinthe host-rangerestrictionandpathogenicityofthese viruseshavebeenidentifiedandaredescribed below,thoughadditionalstudiesareneededto fullyunderstandalloftheadaptivemutations thatcontributetothetransmissionandestablishmentofnewinfluenzaviruslineages.
3.1HemagglutininandReceptorBindingSpecificity
TheviralHAismostlikelythemajorhostrestrictionfactorthatlimitsinfectionandinterspeciestransmissionbecausethecellreceptor–bindingrequirementsoftheproteinaredeterminedbythesialylsugarstructureson glycoproteinsorglycolipids,whichareonthe cellsurfaceanddifferacrossspecies(Klenk etal. 2013;ImaiandKawaoka 2012;deGraaf andFouchier 2014).Themostcommonformof SAistheN-acetylneuraminicacidwithan α2,3 linkageoran α2,6linkagetogalactose,herein reportedasSA-α2,3andSA-α2,6,respectively. HumaninfluenzaAvirusespreferentiallyrecognizeSA-α2,6,whichpredominatesonciliated epithelialcellsthatlinetheupperrespiratory tract.MostavianinfluenzaAvirusespreferentiallyrecognizeSA-α2,3,whichpredominateson epithelialcellsintheintestineandrespiratory tractsofwildbirdsanddomesticbirds.
SpecificaminoacidresiduesatthereceptorbindingpocketoftheHAmediatethisapparent hostpreference,andasfewas1aminoacid mutationcansignificantlychangereceptorbindingspecificityandinfluencevirulence.In particular,aminoacidchangesofglutamine-toleucineatposition226(Q226L)andglycine-toserineatposition228(G228S)affectthesetraits intheH2andH3virussubtypes,andchangesof glutamicacid–to–asparticacidatposition 190(E190D)andasparticacid–to-glycineat position225(D225G)changethereceptorbindingaffinityoftheH1virussubtypefrom avian-to-humanreceptors(RogersandPaulson 1983;Matrosovichetal. 2000;Glaser etal. 2005).Moreover,thedistributionofthe receptortypealsovariesbytissuelocation, includingupperversuslowerrespiratorytract, celltype,andspecies.Inhumans,SA-α2,3is foundoncertainalveolarcells,andtheD225G substitutioninHAofinfluenzaH1N1pdm09 virus,whichwasobservedinsevereandfatal cases,enablestheinfectionofciliatedbronchial cellsinthelowerrespiratorytractbythisvirus andbyviralstrainsofavianorigin(Shinya etal. 2006;Yamadaetal. 2006;Kilander etal. 2010;Chutinimitkuletal. 2010).Nevertheless,theSA-α2,6receptor–bindingpreferenceis consideredessentialforaninfluenzavirusto infectandspreadeasilyamonghumans;thus, thispreferencelimitsavianvirusesfromtransmittingfrombirdstohumans.RecentH5N1 avianisolatesfromEgyptalsobindSA-α2,6, andtheappearanceofthissublineageinthe localbirdpopulationhasbeencorrelatedwith anincreaseinthebird-to-humantransmission efficiency,andthuswithanincreaseinhuman H5N1virusinfections(Watanabeetal. 2011). Moreover,theH7N9virusesthatemergedin Chinain2013possesstheavian-typeresidueat position228,butthehumanvirus–typeQ226L substitution,whichconfersadualavian/human virusreceptor–bindingspecificity(Gao etal. 2013;Shietal. 2013).Althoughthismost likelyexplainstheefficienttransmissionofthese virusesthroughdirectcontact,whichhasbeen seenintheferretandguineapigmodels,these virusesstillrequireadditionaladaptivemutations
forsustainedairbornetransmissionbetween mammals(Watanabeetal. 2013,Zhu etal. 2013;Belseretal. 2013;Zhang etal. 2013;Richardetal. 2013).
Recentevidenceshowsthattheacquisitionof human-typereceptor–bindingspecificityby avianvirusesrequirescompensatorymutations inthestemregionofHAtoguaranteeHAstabilityandtheoptimalpHforfusionandthusdeterminevirustransmissibility(Imaietal. 2012; Herfstetal. 2012).Importantly,aminoacid substitutionsthatlowerthepHthresholdfor fusionmayincreasethereplicationof A/Vietnam/1203/2004(H5N1)intheupper respiratorytractofferretsandplayarolein airbornetransmissionbetweenmammalsbut onlyinthepresenceofanappropriatehumantypereceptor–bindingspecificity(Zaraket etal. 2013).Morethan70mutationsinH1,H2, H3,H5,andH7HAsthataffectthisphenomenon havebeendescribed,whichhighlightshowcomplextheseprocessescanbe(Russell 2014).
HAglycosylationalsoaffectsavarietyof biologicalproperties,includingreceptor-binding specificity.Inparticular,thelossofaglycosylationsiteatposition158–160intheHAofH5N1 facilitatesvirusbindingtothehuman-typereceptor(Wangetal. 2010).Thissiteiscrucialfor H5N1virusvirulenceinmiceandforairborne transmissionbetweenmammals(Imai etal. 2012;Herfstetal. 2012;Gaoetal. 2009). Moreover,Neumannetal.(2012)recently reportedthatH5N1virusesisolatedfromhumans inEgyptlackthisglycosylationsite,whichmay contributetomammaliantransmissibilityof avianH5viruses.Thelossofthisglycosylation siteisalsoreportedinH7N9viruses,thus supportingthevirusabilitytoefficientlyinfect humans(Kageyamaetal. 2013).
3.2OtherVirulenceDeterminants
Factorsotherthanreceptorspecificityinfluence hostsusceptibilityandthepathogenicityofavian influenzaviruses.Afteravirusparticleattaches tothecellreceptorandisinternalizedintoan endosome,thefusogenicactivityofHA
subsequentlyreleasesviralRNPcomplexesinto thecytoplasm.Tothatend,matureHAmustbe cleavedinto2subunits,HA1andHA2,bytissuespecificproteases(KlenkandGarten 1994).The cleavagesiteoftheHAofhumanseasonalinfluenzaAvirusesiscomposedofasinglearginine andtrypsin-likeproteasesthatareproducedby respiratorycellstorecognizeandcleavethis motif.Mostavianvirusesalsopossess1–2 basicaminoacidsatthecleavagesite,andvirus replicationisrestrictedtotheintestinalandrespiratorytracts,thuscausingmildorsubclinical infectioninpoultry.Forthisreason,theseviruses arereferredtoas“low-pathogenic”avianinfluenzaviruses.Incontrast,theHAsofhighlypathogenicavianinfluenzaviruses(HPAIVs)ofH5 andH7subtypesthatemergeingallinaceous poultrycontainapolybasiccleavage-sitemotif thatcanbecleavedbyubiquitousproteases, therebycausingseveresystemicinfectionsand deathinthosespecies(Horimotoetal. 1994). AlthoughHAcleavabilityrepresentsamajorvirulencedeterminantofavianinfluenzaviruses,its roleinmammalsisstillunclear,asnoneofthe humanvirusespossessthispolybasicmotif.
AlthoughHAbindsSA-containingreceptors ontargetcellstoinitiatevirusinfection,NA facilitatesthereleaseofvirusparticlesbycleavingtheSAresiduesfromthecellmembrane. Thus,afunctionalbalancebetweenthe HA-mediatedreceptorbindingandfusionand theNA-mediatedsialidaseactivityisrequired forefficientvirusreplication(BaumandPaulson 1991;CastrucciandKawaoka 1993).In-frame deletionsinthestalkregionoftheNAarefrequentlyfoundinvirusesisolatedfrompoultry, upontransmissionfromwildwaterfowl,andthe shortenedstalklengthofNAisassociatedwith enhancedreplicationintheintestineandrespiratorytractofthosespecies(Campitellietal. 2004; Lietal. 2011;Zhouetal. 2009).Recentexperimentalfindingssuggestthatthismotifalso influencesinfluenzavirustransmission (Blumenkrantzetal. 2013).
Polymeraseactivityalsodeterminesthehost restrictionofinfluenzaviruses,andsomeadaptivemutationsmustoccurduringreplicationin mammalsforanavianinfluenzavirusto
overcomethisrestriction.Inparticular,PB2 proteinplaysakeyroleininfluenzavirulence andadaptationofavianinfluenzavirusesto growthat37 C(thetemperatureofthemammalianrespiratorytract).Aglutamicacid–to–lysine mutationatposition627(E627K)enablespolymeraseactivitiesandviralreplicationin mammals(Subbaraoetal. 1993;Hatta etal. 2007).Thus,thismutationisfrequently selectedduringreplicationofavianvirusesin humansandpoultry.Inaddition,anaspartic acid–to–asparaginemutationatposition 701(D701N)andathreonine-to-alaninesubstitutionatposition271(T271A)ofPB2affectthe replicativeabilityofavianvirusesandare involvedininfluenzavirusadaptationandtransmissibilitytonovelhosts(Lietal. 2005;Bussey etal. 2010;Zhouetal. 2013).Severalstudies haveshowntheroleofPB2ininfluenzavirus transmissibilityandreplacementofthekeyPB2 residuesinthe2009pandemicH1N1virus, H5N1strains,orthe1918pandemicH1N1has beendirectlyrelatedtohigherreplicationin mammalsorrespiratory-droplettransmission (Imaietal. 2012;Herfstetal. 2012;Zhou etal. 2013;VanHoevenetal. 2009;Zhang etal. 2012).Moreover,mostoftheH7N9viruses isolatedfromhumanspossesstheE627Kmutation,whereasthestrainsisolatedfromavianspeciesmaintainthetypicalavianresidue, suggestingthatthismutationemergesduring virusreplicationinhumans(Kageyama etal. 2013;Lametal. 2013;Wangetal. 2014). BesidesthemutationsinkeyPB2residues,those inPB1,PA,andNPoftheviralRNApolymerase complexalsoinfluencethehostrangeofinfluenzaviruses(Gabrieletal. 2005;Watanabe etal. 2009;Manzetal. 2013;Yamayoshi etal. 2014;Chengetal. 2014;Taftetal. 2015).
Finally,PB1-F2andNS1proteinscontribute toviralpathogenicity.Inparticular,PB1-F2 inducesapoptosis,andanasparagine-to-serine substitutionatposition66(N66S)inthe1918 pandemicH1N1andH5N1virusesisassociated withincreasedvirulence(Conenelloetal. 2007). NS1antagonizesinterferonproductionin infectedcells,andtheasparticacid–to–glutamic acidsubstitutionatposition92(D92E)increases
virulenceoftheHPAIH5N1virusinmice(Seo etal. 2002).Severalotheramino-acid substitutionsandthepresenceofaPDZ-ligand domainattheCterminusofNS1enhanceviral replicationandthusactasdeterminantsofvirulence(Jacksonetal. 2008;Twuetal. 2007).
Insummary,severalmolecularfactorsmay contributetopathogenesis,host-rangerestriction,andtransmissionofinfluenzaAviruses. Wildwaterfowlarethemainreservoirofmost influenzaAviruses,andacquisitionoftheadaptivemutationsdescribedabove,duringcirculationinterrestrialpoultry,mayfacilitate transmissiontohumans.Importantly,viruses isolatedfromdomesticpoultryhavelowaffinity forSA-α2,3comparedtothatofvirusesisolated fromwildaquaticbirds,suggestingaroleof thesespeciesintheemergenceofnewinfluenza viruses(Kimbleetal. 2010;Perezetal. 2003; WanandPerez 2006;Costaetal. 2012).Inaddition,pigshavebothhuman-typeandavian-type receptorsontheirtrachealepithelialcells,and thepig’sroleintheemergenceofnovelviral strainsbyreassortmenteventsbetweenviruses ofdifferentanimaloriginshasbeenlargely documented(Itoetal. 1998;Smithetal. 2009). Thus,poultry,quail,andpigsmayserveasnecessaryintermediatehostsforadaptationofavian influenzavirusesfromtheirprimarynaturalreservoirtohumans.
4PandemicInfluenza
Influenzapandemicsoccurwhennewstrainsof influenzavirusesemergeandacquiretheability toefficientlysustainhuman-to-humantransmissiontospreadworldwide.Unlikeregularseasonalepidemicsofinfluenza,pandemicsoccur atunpredictableintervalsandcancausehigh levelsofmortality.Threeinfluenzapandemics occurredduringthetwentiethcentury,andthe emergenceofanewpandemicviruscompletely replacedtheprevioussubtypevirus.The1918 influenzapandemic,alsoknownastheSpanish flu,wasthemostsevere,causingthedeathsof approximately50–100millionpeople.ThatpandemicwascausedbyanH1N1subtypeof
influenzaAvirus,whichwasprobablyofavian origin(Smithetal. 2009;Taubenbergerand Morens 2006).Subsequentpandemicsin1957 and1968,alsoknownastheAsianfluand HongKongflu,respectively,wereassociated withhighmorbiditybutkilledmanyfewerpeople.The1957pandemicvirus(H2N2)contained theHA,NA,andPB1genesofavianvirusorigin fromreassortmentbetweenhumanandavian viruses.The1968pandemicvirus(H3N2) containedanavianHAproteinoftheH3subtype andanovelPB1proteinofavianorigin (Scholtisseketal. 1978;Kawaokaetal. 1989).
In1977,there-emergenceofH1N1viruses aftera20-yearabsenceofthevirusfromcirculation,causedseveraloutbreaksworldwidethat werealmostexclusivelyamongpersonsyounger than25years.Thissuggestedthatolder individualswereprotectedbypre-existing immunity(Wrightetal. 2007;Nakajima etal. 1978).Sincethen,virusesofH1N1and H3N2antigenicsubtypescontinuetocirculate andcauseannualepidemicsinthehuman population.
In2009,theworldexperiencedthefirstpandemicofthetwentyfirstcentury,whichwas initiallyknownas“theswineflu”andcaused byanovelswine-origininfluenzavirus (H1N1pdm09)thatrapidlyreplacedthepreviouslycirculatingseasonalH1N1viruses[Novel Swine-OriginInfluenzaA(H1N1)VirusInvestigationTeam 2009].Althoughthepandemicvirus belongedtotheH1N1subtype,theantigenic divergencebetweenitandtheseasonalH1N1 HAsandthusthelackofcross-immunityina largefractionofthehumanpopulation,causeda rapidglobalspreadofthenovelvirus,resulting ininfectionof20–30%oftheworld’spopulation.TheH1N1pdm09virusisgenetically relatedtovirusesthatcirculateinpigsandwas aproductofreassortmentofinfluenzavirus genesfromNorthAmericanandEurasian swine,avian,andhumanvirusesthatmayhave occurredyearsbeforeemergenceinhumans (Gartenetal. 2009;Smithetal. 2009).Mostly, theH1N1pdm09viruscausedarelativelymild disease,thoughthenumbersofhospitalizations anddeathswerehigheramongyoungerpeople
andpatientswithanunderlyingmedicalconditionwhowereinfectedwithH1N1pdm09than amongthoseinfectedwithseasonalinfluenza (Domı´nguez-Cheritetal. 2009;Vaillant etal. 2009).Sinceitsappearancein2009,the H1N1pdm09virushasestablishedinthehuman populationandcontinuestocirculateasaseasonalH1N1influenzaAvirus.Atpresent,the frequenttransmissionofH1N1pdm09virus fromhumansintoswine,andthehighprevalence ofreassortantswithcocirculatingswineinfluenzavirusesdetectedinpigherdsinseveral countriescontinuetoposeaseriousthreatto publichealth(Simonetal. 2014;Nelson etal. 2015).
Anumberoffindingshavesuggestedarole forpigsintheemergenceofpandemicinfluenza viruses,asintermediatehostsinwhichavian virusesadapttomammalsbeforetheytransmit tohumans.Thelastpandemicprovidedclear evidenceoftheroleoftheseanimalsintheepidemiologyofinfluenzavirusesofpandemic potential;multiplelineagesofinfluenzaA virusescocirculateinpigsandundergofrequent reassortment.Moreover,thelastpandemic highlightedthecontinuedchallengesofinfluenza,intermsofunpredictability.Whenthe influenzacommunitywasalertedtoapotential H5N1pandemic,theemergenceofanH1N1was completelyunexpected.Forthisreason,the H2N2virusthatdisappearedwiththeemergence oftheH3N2virusin1968butcontinuestocirculateinaquaticbirdsstillposesapandemic riskforthosepeoplebornafter1968wholack H2N2-specificimmunologicmemory(Jones etal. 2014).Ourinabilitytopredictthenext pandemicisapublichealthconcern,andonlya continuoussurveillanceprogramtoenhancepreparednesswillhelpmitigatetheeffectsofsuch anunpredictableandpotentiallyseveredisease.
5AnimalInfluenza
Theavailableinformationindicatesthatthewild aquaticbirdsoftheworld,particularlyducks, shorebirds,andgulls(Anseriformesand Charadriiformes)arethenaturalreservoirsof
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