Antiviral Research Present and future arboviral threats

18 Pages·2009·2.54 MB·English

AntiviralResearch85 (2010) 328–345
ContentslistsavailableatScienceDirect
Antiviral Research
journal homepage: www.elsevier.com/locate/antiviral
Review
Present and future arboviral threats
ScottC.Weavera,∗,WilliamK.Reisenb
aDepartmentofPathologyandCenterforBiodefenseandEmergingInfectiousDiseases,UniversityofTexasMedicalBranch,Galveston,TX77555-0609,USA
bCenterforVectorborneDiseasesandDepartmentofPathology,MicrobiologyandImmunology,SchoolofVeterinaryMedicine,UniversityofCalifornia,Davis,CA95616,USA
a r t i c l e i n f o a b s t r a c t
Articlehistory: Arthropod-borneviruses(arboviruses)areimportantcausesofhumandiseasenearlyworldwide.All
Received23August2009 arbovirusescirculateamongwildanimals,andmanycausediseaseafterspillovertransmissiontohumans
Receivedinrevisedform1October2009 andagriculturallyimportantdomesticanimalsthatareincidentalordead-endhosts.Virusessuchas
Accepted16October2009
dengue(DENV)andchikungunya(CHIKV)thathavelosttherequirementforenzooticamplificationnow
produceextensiveepidemicsintropicalurbancenters.Manyarbovirusesrecentlyhaveincreasedin
Keywords: importanceashumanandveterinarypathogensusingavarietyofmechanisms.
Arbovirus
Beginningin1999,WestNilevirus(WNV)underwentadramaticgeographicexpansionintotheAmer-
Emergence
icas.Highamplificationassociatedwithavianvirulencecoupledwithadaptationforreplicationathigher
Epidemic
Flavivirus temperaturesinmosquitovectors,hascausedthelargestepidemicofarboviralencephalitiseverreported
Alphavirus intheAmericas.Japaneseencephalitisvirus(JEV),themostfrequentarboviralcauseofencephalitisworld-
Climatechange wide,hasspreadthroughoutmostofAsiaandasfarsouthasAustraliafromitsputativeorigininIndonesia
andMalaysia.JEVhascausedmajorepidemicsasitinvadednewareas,oftenenabledbyricecultureand
amplificationindomesticatedswine.RiftValleyfevervirus(RVFV),anotherarbovirusthatinfectshumans
afteramplificationindomesticatedanimals,undergoesepizootictransmissionduringwetyearsfollow-
ingdroughts.WarmingoftheIndianOcean,linkedtotheElNin˜o-SouthernOscillationinthePacific,leads
toheavyrainfallineastAfricainundatingsurfacepoolsandverticallyinfectedmosquitoeggslaidduring
previousseasons.LikeWNV,JEVandRVFVcouldbecomeepizooticandepidemicintheAmericasifintro-
ducedunintentionallyviacommerceorintentionallyfornefariouspurposes.Climatewarmingalsocould
facilitatetheexpansionofthedistributionsofmanyarboviruses,asdocumentedforbluetongueviruses
(BTV),majorpathogensofruminants.BTV,especiallyBTV-8,invadedEuropeafterclimatewarmingand
enabledthemajormidgevectortoexpandisdistributionnorthwardintosouthernEurope,extending
thetransmissionseasonandvectorialcapacityoflocalmidgespecies.
Perhapsthegreatesthealthriskofarboviralemergencecomesfromextensivetropicalurbanizationand
thecolonizationofthisexpandinghabitatbythehighlyanthropophilic(attractedtohumans)mosquito,
Aedesaegypti.ThesefactorsledtotheemergenceofpermanentendemiccyclesofurbanDENVandCHIKV,
aswellasseasonalinterhumantransmissionofyellowfevervirus.TherecentinvasionintotheAmericas,
EuropeandAfricabyAedesalbopictus,animportantCHIKVandsecondaryDENVvector,couldenhance
urbantransmissionofthesevirusesintropicalaswellastemperateregions.Theminimalrequirements
forsustainedendemicarbovirustransmission,adequatehumanviremiaandvectorcompetenceofAe.
aegyptiand/orAe.albopictus,maybemetbytwootherviruseswiththepotentialtobecomemajorhuman
pathogens:Venezuelanequineencephalitisvirus,alreadyanimportantcauseofneurologicaldiseasein
humansandequidsthroughouttheAmericas,andMayarovirus,acloserelativeofCHIKVthatproduces
acomparablydebilitatingarthralgicdiseaseinSouthAmerica.Furtherresearchisneededtounderstand
thepotentialoftheseandotherarbovirusestoemergeinthefuture,invadenewgeographicareas,and
becomeimportantpublicandveterinaryhealthproblems.
© 2009 Elsevier B.V. All rights reserved.
Contents
1. Introductiontothearboviruses...................................................................................................................... 329
2. Factorsassociatedwitharbovirusemergenceorinvasion.......................................................................................... 329
3. Examplesofarboviruseswithahistoryofinvasionandemergence................................................................................ 330
∗
Correspondingauthor.Tel.:[phone];fax:[phone].
E-mailaddress:[email protected](S.C.Weaver).
0166-3542/$–seefrontmatter© 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.antiviral.2009.10.008
S.C.Weaver,W.K.Reisen/AntiviralResearch85 (2010) 328–345 329
3.1. WestNilevirus(WNV).......................................................................................................... 330
3.1.1. Distributionandhealthsignificance............................................................................................... 330
3.1.2. FactorsassociatedwithWNVemergence.......................................................................................... 331
3.1.3. Futuretrends.................................................................................................................. 331
3.2. Japaneseencephalitisvirus..................................................................................................... 331
3.2.1. Distributionandsignificance....................................................................................................... 331
3.2.2. Factorsassociatedwithemergence................................................................................................ 332
3.2.3. Futuretrends.................................................................................................................. 332
3.3. RiftValleyfevervirus........................................................................................................... 333
3.3.1. Distributionandsignificance....................................................................................................... 333
3.3.2. Factorsassociatedwithemergence................................................................................................ 333
3.3.3. Futuretrends.................................................................................................................. 334
3.4. Bluetonguevirus(BTV)......................................................................................................... 334
3.4.1. Distributionandsignificance....................................................................................................... 334
3.4.2. Factorsassociatedwithemergence................................................................................................ 334
3.4.3. Futuretrends.................................................................................................................. 335
3.5. Venezuelanequineencephalitisvirus(VEEV).................................................................................. 335
3.5.1. Distributionandsignificance....................................................................................................... 335
3.5.2. Factorsassociatedwithemergence................................................................................................ 335
3.5.3. Futuretrends.................................................................................................................. 336
4. Examplesofarboviralemergenceassociatedwithurbanization................................................................................... 336
4.1. Dengueviruses(DENV)......................................................................................................... 336
4.1.1. Distributionandhealthsignificance............................................................................................... 336
4.1.2. Factorsassociatedwithemergence................................................................................................ 336
4.1.3. Futuretrends.................................................................................................................. 338
4.2. Chikungunyavirus.............................................................................................................. 338
4.2.1. Distributionandhealthsignificance............................................................................................... 338
4.2.2. Factorsassociatedwithemergence................................................................................................ 339
4.2.3. Futuretrends.................................................................................................................. 339
5. Examplesofotherarboviruseswiththepotentialforurbanemergence........................................................................... 340
5.1. Yellowfevervirus(YFV)...................................................................................................................... 340
5.2. Zikavirus(ZIKAV)............................................................................................................................ 340
5.3. Mayarovirus(MAYV)........................................................................................................................ 340
6. Conclusions.......................................................................................................................................... 341
Acknowledgments................................................................................................................................... 341
References........................................................................................................................................... 341
1. Introductiontothearboviruses strategies,suggestingthatthearthropod-bornetransmissionstrat-
egyhasarisenmanytimesduringtheevolutionofRNAviruses.The
Arthropod-borneviruses(arboviruses)aretransmittedbiolog- only known DNA arbovirus is African swine fever virus (Asfarviri-
icallyamongvertebratehostsbyhematophagous(bloodfeeding) dae:Asfarvirus)(CalisherandKarabatsos,1988;Karabatsos,1985;
arthropodvectorssuchasmosquitoesandotherbitingflies,and vanRegenmorteletal.,2000),andthepaucityofDNAarboviruses
ticks. Being, by definition, biologically transmitted, arboviruses suggests that the greater genetic plasticity and higher mutation
must replicate in the arthropod vector prior to transmission, as ratesexhibitedbyRNAviruses(HollandandDomingo,1998)allow
opposedtobeingmechanicallytransmitted,withoutreplicationin themtoaccommodateacycleofalternatingreplicationindisparate
thevector,throughcontaminatedmouthparts(Weaver,1997).Bio- vertebrateandinvertebratehosts.
logicaltransmissioncanbevertical,involvingthepassageofthe Arboviruses circulate among wild animals, and cause disease
virusfromaninfectedfemalevectortobothmaleandfemaleoff- after spillover transmission to humans and/or domestic animals
spring.Horizontaltransmissioncanbevenereal,fromavertically that are incidental or dead-end hosts. Viruses such as dengue
infected male directly to a female vector, as well as oral from a (DENV)andchikungunya(CHIKV)thathavelosttherequirement
femalevectortoavertebratehostviathesalivaduringbloodfeed- forenzooticamplificationnowproduceextensiveepidemics.Many
ing.Thelatterhorizontalmodeoftransmissionismostcommon arbovirusesthathaveevolvedanddiversifiedinthetropicshave
forthemajorityofarbovirusesandinvolvesinfectionofthevector producedvirulentandinvasivestrainsthathavecausedmajorout-
alimentarytractfollowingaviremicbloodmeal,disseminationof breaksattemperatelatitudes.Theabilityofthesevirusestocause
thevirusinthevector,andeventualvirusreplicationinthesalivary humandiseasedependsonfactorsrangingfromepidemiologyto
glands,followedbytheinjectionofinfectioussalivaduringblood viralgenetics.Herein,wereviewhowsomeofthesefactorshaveled
feeding. toarboviralemergencesandresultedinhumandisease,byusing
ThearbovirusesincludeawidevarietyofRNAvirustaxainclud- severalexamplesofviruseswithaknownepidemichistoryaswell
ing the alphaviruses (genus Alphavirus, one of two genera in assomethathaveapoorlyrecognizedepidemicpotential.
the family Togaviridae); the flaviviruses (genus Flavivirus, one of
three genera in the family Flaviviridae); the bunyaviruses (Bun- 2. Factorsassociatedwitharbovirusemergenceorinvasion
yaviridae:Bunyavirus),nairoviruses(Bunyaviridae:Nairovirus)and
phleboviruses(Bunyaviridae:Phlebovirus);theorbiviruses(oneof For arboviral amplification to progress rapidly to epidemic
ninegenerainthefamilyReoviridae);thevesiculoviruses(oneofsix levels, competent vector and vertebrate host populations must
generainthefamilyRhabdoviridae)andthethogotoviruses(oneof intersectrepeatedlywithinapermissiveenvironment.Thisfocus
fourgenerainthefamilyOrthomyxoviridae).ThesegroupsofRNA ornidusoftransmissionmaybetemporallyand/orspatiallycon-
viruses have a variety of types of RNA genomes and replication strained by host or virus ecology, and may vary in complexity
330 S.C.Weaver,W.K.Reisen/AntiviralResearch85 (2010) 328–345
depending upon virus epidemiology. Zoonoses exploiting com- conducive to vector population expansion and transmission, but
plexruralorsuburbanecosystemsmayhavemultiplevectorsand alsointhecreationofurbanheatislandsthatfacilitatetransmis-
infectavarietyofvertebratehostspecies,whereasanthroponoses sion.
(diseases transmitted from humans to other animals) exploiting Emergenceofanarbovirusmayrequirechangeinoneorsev-
urbanenvironmentsmayrequireonlyasingleanthropophilicvec- eraloftheabove-mentionedfactors.Inthisreview,weanalyzethe
tor and human hosts for amplification. Humans are exposed to cascade of factors that have facilitated the recent local and cir-
arboviruseswhentheyinvaderuralenvironmentsorwhenbridge cumglobal emergence of selected arboviruses. These arboviruses
vectorsbringvirusesintoperidomesticenvironments.Incontrast, were chosen because of their public or veterinary health signifi-
for many anthroponoses, human habitations form the nidus of cance,thecombinationsoffactorsleadingtotheiremergence,and
transmission. Frequently arboviruses persist at low or even ten- asexamplestohelpunderstandthecriticalfeaturesofemerging
uousmaintenancelevelsuntilsomechangeinsingleormultiple arboviralrisksandhowtheymaybemitigated.Finally,weconclude
factorsfacilitatesrapidandwidespreadamplification.Althoughin- withafewexamplesofarbovirusesthathavebeenlargelyignored,
depthreviewsofthesefactorshavebeenpublished(Committeeof butpossessthepotentialtoemerge.Throughoutthisreview,our
EmergingMicrobialThreatstoHealth,2001;DavisandLederberg, understanding of the temporal and spatial patterns of invasion
2001; Fauci, 2005; Gubler, 1998; Mackenzie et al., 2001), recent andemergencehasbeencomplicatedbydiagnosis,retentionand
circumglobalchangesinclimateandotheranthropogenic(derived sequencingofavailablearchivalstrains,andmethodsofcharacter-
from human activities) factors, epidemiology, and viral genetics ization.
havestimulatedtheneedtoupdateandextendinformationonthe
roleofthesechangesintheemergenceofarboviruses. 3. Examplesofarboviruseswithahistoryofinvasionand
Emergingorinvadingarbovirusesmayamplifytoepidemiclev- emergence
els because natural systems have been perturbed by changes in
viralgenetics,hostorvectorpopulationcompositionordynamics, 3.1. WestNilevirus(WNV)
and/or environmental structures that frequently are of anthro-
pogenic origin. Often, outbreaks of emerging arboviruses can be 3.1.1. Distributionandhealthsignificance
relatedtorelativelysmallchangesinviralgeneticsortotheintro- WestNilevirus(WNV)ispositionedtaxonomicallywithinthe
ductionofnewstrainsthathaveincreasedvirulenceandviremia Japanese encephalitis virus (JEV) serocomplex in the genus Fla-
levels in vertebrates, thereby expanding host range and increas- vivirus.Itismaintainedandamplifiedinnaturewithinanenzootic
ing amplification potential. Alternatively, viral genetic changes transmissioncycleamongpasseriformbirdsandCulexmosquitoes,
mayenhancevectorcompetenceandthereforetransmissionrates. withoutbreakscausedbytangentialorspillovertransmissionto
Changesinvertebrateorvectorhostspeciescompositionmaybe equidsandhumans,‘dead-end’hoststhatproduceviremiasinad-
related to environmental change expanding old or creating new equateformosquitoinfection.WNVisdistributedcircumglobally,
niches,ortoinvasionsrelatedtotravelorcommerce.Vectorrange with two main genetic lineages: Lineage 1 is widely distributed
extensionsintopermissiveenvironmentsfrequentlyarefollowed andhighlyinvasive,whereasLineage2appearstohaveremained
byinvasionsofthearbovirusestheytransmit.Theseinvasionstyp- enzooticinAfrica(Fig.1).Lineages3and4havebeendescribed
icallyhavebeenfacilitatedbytravelandcommerce,especiallyover fromsingleisolatesfromCentralEurope,buttheirtaxonomicsta-
repeatedlytraveledroutes.Receptivityofanareatoviralinvasion tusandmedicalimportanceareunclear,whereasLineage5appears
mayberelatedstronglytoenvironmentalconditionsconduciveto tobeconfinedtoIndia(Krameretal.,2008).Recognizedsubclades
viralreplication.Recently,seasonaldurationsandgeographiclimits ofLineage1include1athatiswidespreadthroughoutAfricaand
havebeenexpandingastheearthwarms.Expandingurbanization theMediterranean,Lineage1b(akaKunjinvirus)thatisrestricted
hasresultednotonlyintheextremeconcentrationsofsuscepti- toAustralia,andLineage1cthatisfoundinCentralAsiathrough
blehumanhosts,frequentlylivingundersocioeconomicconditions thecentralhighlandsofIndia(Lanciottietal.,2002).Historically,
Fig.1. ProbabletemporalsequenceanddispersalroutesofWNVfromitsproposedcenteroforigininsub-SaharanAfrica(Lanciottietal.,2002).
S.C.Weaver,W.K.Reisen/AntiviralResearch85 (2010) 328–345 331
the northern distribution of Lineage 1a in Europe and Asia and a very closely related New World genotype that is transmitted
the southern distribution of 1a and 2 in Africa were thought to moreefficientlybyCulexmosquitoes(Moudyetal.,2007),espe-
be constrained by minimum temperature requirements for effi- ciallyathightemperatures(Kilpatricketal.,2008).NorthAmerican
cientreplicationinthemosquitovector,whereaselsewhereWNV Culexaremoderatelycompetentlaboratoryvectors(Goddardetal.,
isreplacedbyothermembersoftheJEVserocomplexfromcen- 2002;Turelletal.,2000,2001)andthereforerequireelevatedavian
tralthrougheasternAsiatotheTorresStraight;KunjinandMurray viremiasforeffectiveinfection(Reisenetal.,2005).In2003,the
ValleyencephalitisvirusesreplaceJEVsouthoftheTorresStraight WNVepicentermovedwestintotheprairiebiomesandthewest
(Hall et al., 2002). Previously, the wide distribution of St. Louis Coast,whereCulextarsalisemergedasasignificantvector(Reisen
encephalitisvirus(SLEV)intheNewWorldmayhavedeterredthe etal.,2004).Amplificationandthehighincidenceofhumaninfec-
introduction of WNV, although there has been no evidence pre- tionintheCanadianandU.S.prairiebiomeswereassociatedwith
sentedthatWNVwasintroducedotherthanoncein1999. Cx.tarsalis,aswellaswithabove-averagesummertemperatures
thatexceededprevious30yearaverages(Reisenetal.,2006).
3.1.2. FactorsassociatedwithWNVemergence Like SLEV and eastern (EEEV) and western (WEEV) equine
Commerceandtheinternationaldispersalofmosquitoesinthe encephalitisviruses,WNVseemsto“disappear”intotheNeotropics
Culexpipienscomplex(Fonsecaetal.,2004;Vinagradova,2000),the withlittleevidenceofhumandisease.Extensivesearchesamong
intentionaland/orunintentionalintroductionofthehousesparrow resident and migratory birds have discovered antibody-positive
[Passerdomesticus(Zimmerman,2002)],climatewarming,andper- individualsatalowrate(Boschetal.,2007;Deardorffetal.,2006;
hapsthedeclineofSLEVmayhavesetthestagefortheemergence Dupuisetal.,2003,2005;Farfan-Aleetal.,2004,2006;Lorono-Pino
of WNV in Europe and the New World. Although a wide variety et al., 2003) and blood supply examinations have indicated lim-
of mosquitoes in the genus Culex have become involved region- itedhumaninfections(Sanchez-Guerreroetal.,2006).Outbreaks
allyinWNVtransmissionwithinNorthAmericaandmaybehighly in humans or equids were not recorded until studies were done
competent vectors, members of the commensal Cx. pipiens com- in the southern temperate latitudes of Argentina (Morales et al.,
plex appear to be associated most closely with urban/suburban 2006).
outbreaksandhumaninfection(Komar,2003).Similarly,theubiq- Insummary,thelarge-scaleepidemicofWNVinNorthAmerica
uitous and aggressively invasive house sparrow is multibrooded wasenabledbythehighamplificationphenotype(associatedwith
andahighlycompetenthostformostWNVstrains(Krameretal., high avian virulence) of the invading virus, the naïvete of North
2008; Langevin et al., 2005; Nemeth et al., 2009), providing the American birds, the competence of North American Cx. pipiens
availability of an almost circumglobal maintenance and amplifi- forverticalandhorizontaltransmission,successfuloverwintering
cation host. Replication of WNV in the poikilothermic mosquito within the mosquito host (Anderson et al., 2006, 2008), and the
hostistemperature-limitedandprogressesmosteffectivelyunder slight,butsignificant,evolutionarychangesthatfacilitatedrapid
warmmidsummerconditions(Kilpatricketal.,2008;Reisenetal., transmissionduringsummertemperatures(Kilpatricketal.,2008)
2006).Climatechangeatnortherntemperatelatitudesrecentlyhas thatmayhaveenablednorthernexpansionintoCanada.
made these areas more conducive to WNV invasion. In the New
World through the mid-1970s, large and fairly widespread SLEV 3.1.3. Futuretrends
epidemics(Monath,1980)mayhaveelevatedavianherdimmu- WNV is now one of the most broadly distributed arboviruses
nitysufficienttoprecludetheintroductionandestablishmentof in the world, being found on all continents except Antarctica
historicLineage1aWNVstrains. (Kramer et al., 2008). Invasion typically has been followed by
Recent outbreaks of WNV were recorded throughout the rapidsubsidenceofdisease(Hayesetal.,2005),butthenperiodic
Mediterranean and then Romania, Central Europe and Russia, resurgenceswheneveradequatevectorandsusceptibleavianpop-
where Cx. pipiens appeared to be the primary vector (Fyodorova ulationsintersectunderpermissiveclimaticconditions.Equidsare
etal.,2006;Savageetal.,1999).Evenduringyearswhenhuman nowprotectedbywidespreadintentionalandnaturalvaccination;
outbreaks were not recorded there, epiornitics followed the however,themotivationforhumanvaccinedevelopmentmaybe
introduction of WNV into Israel by southbound migrating birds limitedbythelowattackrateinhumansthathasbeendocumented
(Malkinsonetal.,2002).Someoftheseviralstrainshaveappeared followingepidemics(PrinceandHogrefe,2003).Inthenearterm,
tobecomeprogressivelymorevirulentforbirds(Malkinsonetal., protectionofthepublichealthwillcontinuetorelyonmosquito
2002)andhumans. control,publiceducation,and,hopefully,newtherapeutics.
WNVwasintroducedintoNewYorkduringthesummerof1999,
and the nucleotide sequence of the invading strain was related 3.2. Japaneseencephalitisvirus
closelytoa1998isolatefromIsraelthatcausedwidespreadillness
in geese (Lanciotti et al., 1999) and contained a mutation in the 3.2.1. Distributionandsignificance
helicasegenethatcausedhighviremiaandmortalityinAmerican JEVisthemostfrequentcauseofmosquito-borneencephalitis
crows(Braultetal.,2007).Interestingly,theresultingNYoutbreak globallyandtheonlyencephalitisvirusagainstwhichlargepor-
thatseemedtobeamplifiedamonghousesparrows(Komar,2000; tionsofhumanpopulationsinmultiplecountriesarevaccinated.
Komaretal.,2001)wasassociatedwithwidespreaddeathinAmer- Thepublichealthsignificanceandpossiblytheglobaldistribution
icancrows(Hochachkaetal.,2004),andwastransmittedprimarily ofJEVhavebeenprogressivelyexpanding.Sinceitwasfirstdocu-
byCx.pipiensmosquitoes(Nascietal.,2001b).WNVoverwintered mentedasanimportantcauseofencephalitisinJapaninthelate
successfullyindiapausingCx.pipiens(Nascietal.,2001a)andper- 1800s,significantincursionshaveoccurredintoCentralAsia(Burke
haps by bird-to-bird transmission at communal American crow andLeake,1988)(Fig.2).Currently,morethan3billionpeoplein
roosts (Dawson et al., 2007). By 2002, WNV had spread to the AsiaresideinareasatriskofJE,withanestimated30,000–50,000
MidwestandwasassociatedwithlargeoutbreaksinIllinois,trans- casesoccurringannually(Erlangeretal.,2009).
mittedbyCx.pipiens,andinLouisiana,transmittedbyitssouthern Taxonomically,Japaneseencephalitisvirusisplacedwithinthe
form,Cx.quinquefasciatus.AsWNVexploitednewgeographicareas, genusFlavivirusandisthetypevirusfortheJEVserocomplexthat
different,buthighlycompetent,avianhostssuchasbluejaysand alsocontainsWNV,MurrayValleyencephalitisvirusandSLEV.JEV
American robins became recognized as important amplification is maintained within an ardeid bird – Culex mosquito transmis-
hosts(Hameretal.,2009;Kilpatricketal.,2006).Concurrently,the sioncycleandisamplifiedwithinadomesticswine–Culexcycle.
foundingNY99strainwasreplacedbyWN02(Davisetal.,2003), CulexmosquitoestangentiallytransmitJEVtoequidsandhumans,
332 S.C.Weaver,W.K.Reisen/AntiviralResearch85 (2010) 328–345
Fig.2. ProbablesequenceanddispersalroutesofJEVfromitsputativecenteroforiginintheMalayArchipelago(BurkeandLeake,1988;Solomonetal.,2003).Patternof
lineagedispersalwasdifficulttotrace.
whicharedead-endhostsforthevirus(BurkeandLeake,1988). recognized in Japan starting in the late 1800s (Burke and Leake,
TheknowndistributionofJEVrangesfromKoreasouthtoAustralia 1988; Erlanger et al., 2009; van den Hurk et al., 2009). Tracing
andthennorthwestintoPakistan(Fig.2).Thedistributionofthe JEV (mostly Lineage I) as an emerging health problem from the
primarymosquitovector,Culextritaeniorhynchus,overlapsmostof first epidemics in Japan, sequential outbreaks were documented
thisgeographicalarea,whereitisveryabundantinassociationwith innortheast(Korea,ChinaandTaiwan),southeastAsia(Vietnam,
riceandotherirrigatedcrops.Ahighlycompetentlaboratoryvec- Thailand) and most recently central (Nepal, India, Pakistan) and
tor(Hammonetal.,1949;Okunoetal.,1975),Cx.tritaeniorhynchus southcentralAsia(SriLanka)(BurkeandLeake,1988;Erlangeret
bloodfeedspredominantlyonlargemammals(Mitchelletal.,1973; al.,2009).ThisrapidandwidespreadexpansionofJEVwasasso-
ReisenandBoreham,1979),includingswine,andhasbeenimpli- ciated closely with increases in human populations, in acreage
catedinamplificationandtangentialtransmission(KonoandKim, of irrigated rice, and in pig farming (Erlanger et al., 2009; van
1969).OtherCulexinthevishnui,bitaeniorhynchusandpipienscom- denHurketal.,2009).InendemicareasofJapan,theavian-Culex
plexesalsohavealsobeenincriminatedasvectors,buthavemore maintenancecyclemaybebypassedwhenverticallyinfectedCx.
limitedgeographicdistributions.Expandingirrigatedricecultiva- tritaeniorhynchus (Rosen et al., 1989) directly initiate the ampli-
tionhasenabledincreasesinmosquitovectorpopulationsaswell fication cycle in pigs after terminating diapause (Hayashi et al.,
asthedistributionandabundanceoftheardeidmaintenancehosts, 1973). The invasion of India, Pakistan (Igarashi et al., 1994) and
including the black-crowned night heron (Nycticorax nycticorax) Nepal(Hendersonetal.,1983),whereswinefarmingislimited,may
andtheAsiancattleegret(Bubulcusibiscoromandus)(Buescherand indicateanexpandingroleforbirdsinJEVamplification(Boyleet
Scherer,1959;Buescheretal.,1959;Solomonetal.,2003). al.,1983;Jamgaonkaretal.,2003;Rodriguesetal.,1981;Soman
andMourya,1985;Somanetal.,1986,1977).Althoughtypically
3.2.2. Factorsassociatedwithemergence associatedwithlowlandricefarmingintheouterTeraiofNepal,
ThereisadiscrepancybetweentheproposedJEVevolutionary JEVoutbreaksrecentlyhaveoccurredathighelevationsinKath-
centeroforigin(Solomonetal.,2003)anditspatternsofexpand- mandu Valley, where the virus now is endemic (Partridge et al.,
ingdistributionasapublichealthproblemastracedbyoutbreaks 2007; Zimmerman et al., 1997). JEV Lineages I and II also have
(BurkeandLeake,1988).Ofthefivemajorgeneticlineages,only movedprogressivelyeastintoNewGuinea,withrecentincursions
Lineages I–III have been found in subtropical or temperate lati- across the Torres Straight into northern Australia (Hanna et al.,
tudesandareassociatedwithoutbreaksofneuroinvasivedisease; 1999;Mackenzieetal.,2002).
ancestral Lineages IV and V appear restricted to the Indonesian
archipelago,wherewithLineagesI–III,theycauselimitedandspo- 3.2.3. Futuretrends
radichumancases(Fig.2).Because‘virginsoil’outbreakstypically AirtransportofmosquitoeswastheprobablecauseofJEVout-
havebeenaccompaniedbyextensiveneuroinvasivediseaseinall breaks on isolated Pacific Islands such as Guam (Hammon et al.,
humanagegroupsaswellasinpigs,itisunlikelythatJEVwasa 1958)andSaipan(Mitchelletal.,1993),demonstratingthepoten-
majorpublichealthprobleminnorthernAsiauntilepidemicswere tialofthisvirustoinvadenewareassuchasthewestcoastofthe
S.C.Weaver,W.K.Reisen/AntiviralResearch85 (2010) 328–345 333
USA.Here,susceptiblemosquitoesandavianhostscouldconceiv- ritania(Fayeetal.,2007;Nabethetal.,2001).RVFVisolatesfrom
ablyallowestablishmentbeforecurrentsurveillanceandcontrol bothoutbreaksweredistinctandmonophyletic,perhapsindicating
programswoulddetectandeliminatethisvirus(Nettetal.,2009; dispersalandamplificationbyasinglestrain(Birdetal.,2008).
vandenHurketal.,2009).WiththespreadofJEVintomuchofthe
Indiansubcontinent,otherdestinationsservedbyfrequentroutes 3.3.2. Factorsassociatedwithemergence
of commerce or passenger air travel, such as Africa and Europe, RVFVismaintainedinanenzooticcycleamongwildlife,such
also could be at risk. Tracing the recent, rapid dispersal path of asAfricanbuffaloes,andawidevarietyofmosquitospecies(>30
chikungunyavirusservestodemonstratetheimportanceofroutes species,sixgenera).Transmissionisenzooticduringmostyears,but
offrequenttravelforvectorandarbovirusinvasions(Powersand epizooticduringwetyears,especiallyfollowingdroughts.Appar-
Logue,2007;Simonetal.,2008). ently,virusismaintainedbetweenrainyseasonsandbetweenhigh
rainfallyearsbyverticaltransmissiontodesiccationresistanteggs
3.3. RiftValleyfevervirus of several floodwater Aedes species, especially Aedes macintoshi
(Linthicumetal.,1985a).Highwateryearsinundateseveralprevi-
3.3.1. Distributionandsignificance ousseasonsofeggs,givingrisetolargenumbersofmosquitoesand
Rift Valley fever virus (RVFV) is classified within the genus perhapsmultiplevirallineages(Birdetal.,2008).Infectionrates
Phlebovirus in the family Bunyaviridae and causes intermittent amongAedesadultsrearedfromfield-collectedlarvaetypicallyare
epizootics and sporadic epidemics, primarily in east Africa (Bird low (Linthicum et al., 1985a), therefore requiring extensive hor-
et al., 2009; Daubney et al., 1931). Infection causes severe and izontal amplification for RVFV maintenance. The large variety of
often fatal illness in sheep and cattle, with occasional spill over wildlifenaturallyinfectedwithRVFVwouldseemtosupportthis
toincludeotherdomesticanimalsandhumans.Camelsalsofre- notion.
quentlybecomeinfected,butseemtosufferlessillnessandlower WarmingintheIndianOceanislinkedcloselytotheElNin˜o-
abortion rates than other livestock. In 1–2% of affected humans, SouthernOscillation(ENSO)inthePacificandisfollowedbyhigh
RVFprogressestoseveredisease,includinghepatitis,encephalitis, rainfalleventsintheRiftValleythatarepredictiveofRVFVout-
retinitis, blindness, and/or a hemorrhagic fever; the case fatality breaks (Linthicum et al., 1999). Widespread flooding, apparent
rateisapproximately10–20%(Madanietal.,2003). from satellite imagery by examining the normalized difference
Historically,RVFVwasrestrictedtosub-SaharaneasternAfrica, vegetationindexdata,triggersthesimultaneoushatchingoflarge
especially Rift Valley of the Kenya and Tanzania (Meegan et al., numbersofAedeseggs,rapidlyproducingacohortofbloodfeed-
1989),whereoutbreaksarecausedbymultiplelineagesofthevirus ing adults, some of which are infectious with RVFV and able to
(Birdetal.,2008).Subsequentoutbreakswithhumaninvolvement transmitthisinfectiontoruminants.Bothwildanddomesticrumi-
havebeendocumentedinSouthAfrica,theNileValleyfromSudan nantsaredrawnordrivenbyherdsmentothesenewsourcesof
to the Egyptian delta, and the Saudi Arabian peninsula (Fig. 3). water and grass, bringing susceptible hosts into close proximity
The1977–1979outbreakinEgyptwasespeciallydevastating,with withinfectiousmammal-feedingAedesmosquitoes(Linthicumet
morethan200,000humaninfectionsand600deathsandlossesin al.,1985b).Thesenewmosquitohabitatsalsoarecolonizedbyother
livestock>$100Matthattime(Meeganetal.,1978).Tenyearslater effectivemosquitovectorsthattakelongertomatureandthere-
anotherlargeoutbreakoccurredinWestAfricacenteredinMau- foreemergewhenthefirstgroupsofinfectedruminantsbecome
Fig.3. TemporalpatternsofdispersalbyRVFVinAfrica(Birdetal.,2009).Datesindicatetheearliestdetectionandpossibleestablishmentofvirusineacharea.
334 S.C.Weaver,W.K.Reisen/AntiviralResearch85 (2010) 328–345
viremic,furtherspreadingthevirustonewhosts.Theconcordance forresistancetodiseaseinAfricanwildlife.ThedistributionofBTV
between the rainy season and the calving of wild and domestic hasbeendividedintothreeepidemiologicalzones,basedonthe
ruminants assures that highly susceptible host populations are occurrenceofclinicaldisease:(1)anenzooticzoneinthetropics
available to be fed upon by infectious mosquito vectors during whereinfectioniscommonbutclinicaldiseaseisrare,(2)anepi-
warmhumidweatherconditionsconducivefortransmission. zooticzoneattemperatelatitudeswherediseaseoutbreaksoccur
frequently,and(3)anincursivezonewhereinfectionisinfrequent
3.3.3. Futuretrends becauseclimateand/orvectorspeciestypicallyarenotsuitablefor
Large‘virginsoil’outbreaksinMauritania,EgyptandSaudiAra- transmission(GibbsandGreiner,1988).
bia have demonstrated the ability of RVFV to escape traditional
enzootic areas and invade naïve populations. Routes of disper- 3.4.2. Factorsassociatedwithemergence
salhavenotbeenfullyestablished,butthemovementofviremic The veterinary epidemiology of BTVs in North America and
camels along trade routes has been suspected (Hoogstraal et al., Europeiscomplexandrelatedstronglytovirusandvectorgenetics
1979) as well as vectors carried on storm fronts (Sellers et al., and distributions, overwintering mechanisms, and perhaps cli-
1982).Beforetheonsetofseriousclinicaldisease,humansdevelop mate change. Based on a survey of cattle at slaughter, at least 5
viremiassuitabletoinfectsusceptiblemosquitoes.Uncontrolledair viruses(BTV-2,-10,-11,-13,-17)werefoundintheU.S.(Metcalf
travelthereforecouldintroduceRVFVintoothercontinentssuch etal.,1981),withprevalencegreatestinthesouthwestandleast
asNorthAmericaorEuropewheresusceptiblewildanddomestic prevalenceinthenortheast,wheretheprimaryvector,Culicoides
hostsandsuitablevectormosquitoesreside(Garganetal.,1988; sonorensis,isreplacedbythelesscompetentvector,Culicoidesvari-
Turelletal.,2008). ipennis (Jones and Foster, 1978; Tabachnick et al., 1996). Other
ExtensivestudiesbytheUSDAandNASAhaveshownthattrack- species such as Culicoides insignis are suspected as vectors at
ingENSOinthePacificOceanprovidesanearlywarningofwarming southern latitudes. Differences in vector competence within the
intheIndianOcean,heavyrainfallintheRiftValleyandoutbreaks variipennis species complex have been related to a midgut bar-
ofRVFV(Anyambaetal.,2009).SeveralvaccinesforRVFVhavebeen riertoinfection(Tabachnicketal.,1996).DistributionofBTVsin
developedandappeareffective(Birdetal.,2009),however,local thenorthernprairiestatesandCanadaseemslimitedbythetem-
agencieshavebeenreticenttopre-emptivelyprecludeoutbreaks peraturerequirementsforvirusreplicationinthevector(Mullens
byvaccinationcampaigns.Failuretocontaintheseoutbreakspro- et al., 1995), with transmission limited to summer periods with
videsasourceofvirustoseedoutbreaksintootherareasofAfrica temperatures>15◦C.RecentwarmingtrendsinCanadahavefacil-
andtheMiddleEastaswellastherestoftheworld.Futurecon- itated the population dynamics of C. sonorensis (Lysyk, 2007;
tainmentofRVFVwillrequirepre-emptivevaccinationoflivestock Lysyk and Danyk, 2007) and may allow more frequent incur-
in Africa and carefully regulated travel restrictions on livestock, sions and perhaps the eventual establishment of BTV. Little is
wild animals and perhaps humans from affected areas. With a knownaboutvariationinthetemperaturerequirementsofdiffer-
high potential impact on wildlife, domestic animal and human entBTVs.
health,failuretocontainRVFVcouldseriouslyimpactveterinary Until1996,EuropewasconsideredBTV-freeandinternational
andhumanhealthinAsia,EuropeandtheNewWorldandhave trade restrictions by the European Union created huge annual
economicconsequencesfarexceedingthoseofthewaningWNV financiallossestoenzooticpartsofNorthAmericafromtheloss
outbreak. oftradeofanimalsandanimalproducts.Occasionalincursionsof
BTVsintoSpain,PortugalandTurkeyhavebeenrelatedtoprevail-
3.4. Bluetonguevirus(BTV) ingwindsoriginatinginNorthAfricaortheMiddleEast(Sellers,
1980; Sellers et al., 1979, 1978). BTV apparently became estab-
3.4.1. Distributionandsignificance lishedinEuropeafterclimatewarmingenabledthemajorvector,
BTVsareclassifiedwithinthegenusOrbivirus(familyReoviri- Culicoidesimicola,toexpandisdistributionnorthwardtoinclude
dae)andcurrentlyconsistofatleast24virusesclusteredwithin partsofsouthernEuropeeastintoTurkey(Purseetal.,2005).Coin-
10distinctlineages(Schwartz-Corniletal.,2008).BTVscauseeco- cidentally, five strains became established in the Mediterranean
nomically significant disease in ruminants and, because of this during1998–2005.Thesestrainsseemtohaveinvadedfollowing
veterinary economic impact were placed on list-A by the Office routesfromTunisiaandNorthAfrica(BTV-2,-4)andfromTurkey
InternationaldesEpizooties(OIE),limitingtradeofanimalprod- from the Middle East (BTV-1, -4, -9, -16) (Purse et al., 2005). In
uctsfromaffectedareas.BTVsaremaintainedwithinanenzootic August 2006, BTV-8 invaded central and northern Europe, areas
cycleamongbitingmidgesinthegenusCulicoides(familyCerato- north of the known distribution of C. imicola (Saegerman et al.,
pogonidae)andvariousruminantspecies,almostallofwhichare 2008).Thison-goingoutbreakapparentlyinvolvestransmissionby
susceptibletoinfection.Historically,itwasthoughtthattheBTVs otherCulicoidesspecies,includingCulicoidesdewulfiandmembers
evolvedandwerecontainedwithinAfricauntilthe1940s,whenthe oftheCulicoidesobsoletusandCulicoidespulicariscomplexes.How-
firstMediterraneanoutbreakoccurredinCyprus.However,subse- ever,incriminatingfieldinfectionandvectorcompetencedatahave
quent studies have found BTVs widely distributed in the tropics beenscarce(Carpenteretal.,2008,2009).Climateinthisareaof
but not frequently associated with illness and therefore mostly Europehasexperiencedastrongwarmingtrend(Purseetal.,2005)
undetected.Clinicaldiseaseismostprevalentindomesticsheep, andundoubtedlythischangehasshortenedtheextrinsicincuba-
especiallythoseofEuropeanancestry(Purseetal.,2008).Typically, tion period of the virus within the Culicoides vector (Mullens et
cattle rarely show clinical illness and are considered a reservoir al.,1995),andthegonotrophic(bloodfeedingandreproductive)
host, whereas goats usually do not develop overt disease (Gibbs cycleofthevector,therebyincreasingthefrequencyofvector–host
andGreiner,1988);however,duringtherecentincursionofBTV- contactandextendingthedurationofthetransmissionseason.
8intowesternEurope,clinicalillnessincattlewascommonand ForBTVtobecomeestablishedattemperatelatitudes,itmust
associatedwithalowcasefatalityrate(http://www.oie.int). be able to overwinter locally. Studies on Culicoides indicate that
WildruminantsinNorthAmerica,includingdeer,pronghorns adultsarenotactiveduringwinter(Takkenetal.,2008)andverti-
anddesertbighornsheep,developseveredisease,whereasAfrican caltransmissionofBTVremainsundocumented(Whiteetal.,2005).
wildlifeseemsmostlyunaffected.Thisdisparityindiseasesuscep- Incontrast,ruminantsdeveloplonglastingchronicinfections,but
tibility supports the notion that Africa is the center of origin for recrudescence mechanisms are poorly understood. Possibly, the
BTVandthatitsenzooticcirculationthereseeminglyhasselected cellularimmuneresponseofthehosttoCulicoidesbloodfeeding
S.C.Weaver,W.K.Reisen/AntiviralResearch85 (2010) 328–345 335
couldtriggerthereleaseofBTVatthebiteareaandtherebyallow
co-orlaterfeedingfliestoingestthevirusandrenewtransmission
inthespring(Purseetal.,2008).Althoughnotasyetsupportedby
fieldevidence,thismechanismisintriguingbecauseitsynchronizes
fly blood feeding activity and viral recrudescence. Alternatively,
virus may overwinter in transplacentally infected calf and lamb
fetuses that are viremic at birth (Backx et al., 2009; Gibbs et al.,
1979;Worwaetal.,2009).
3.4.3. Futuretrends
Introductions and subsequent dispersal of BTVs most likely
will continue due to intercontinental animal and animal prod-
uct commerce as well as from windborne flies (Hendrickx et al.,
2008; Sellers, 1980). Climate warming most likely will expand
theepizooticzoneintonortherntemperateregionsandmovethe
zoneofincursionfurthernorthward.Theexpandingdistributionof
variousBTVsmayeventuallyresultintheremovaloftradeembar-
goes,becausemostareasoftheearthwillsupportsomelevelof
enzooticity.ThreeoptionsremainformitigatingtheBTVproblem:
molecularengineering/selectivebreedingoflivestocktoincrease
resistance to disease, vector control and vaccination. Molecular
biologymayholdtheanswerifcurrentsusceptiblebreedsofcattle
andsheepcanbegeneticallymodifiedtoimpartresistance.Treating
wastewaterpondsorotherknownlarvalhabitatsofspeciessuchas
C.sonorensisinthearidsouthwesternUSAhaspromise;however,
controlofotherCulicoidesthatdevelopinlessobvioushabitatssuch
asmoistpastureswillbeamuchgreaterchallenge,especiallyin
Europe.Chemicaldipshavebeenusedtocontroltickinfestations
and perhaps a similar approach with other compounds could be
usedtoreduceoreliminateadultfliesorpreventbiting.Complex
immuneinteractionsagainstasmanyas24virusesmakesvaccine
developmentchallenging,butperhapsvaccinescanbedeveloped
againstspecificstrainsofBTVwithaparticularlyhighpotentialfor
invasion. Fig.4. Geographicdistributionofepidemic/epizooticVEEVstrainsresponsiblefor
majoroutbreaks,andenzooticVEEcomplexstrainsisolatedprincipallyinswamp
orforesthabitats.
3.5. Venezuelanequineencephalitisvirus(VEEV)
3.5.1. Distributionandsignificance highlyincapacitatingDEN-likefebrileillnessthatoccasionallyleads
VEEVisanalphavirus(Togaviridae:Alphavirus)foundonlyinthe tofatalencephalitis,mainlyinchildren.
NewWorld(Fig.4).ItisthetypespecieswithintheVEEcomplex
ofalphavirusesthatincludes7differentspeciesandmultiplesub- 3.5.2. Factorsassociatedwithemergence
typesandvarieties(Weaveretal.,2004).EnzooticsubtypesIDand TheemergenceofepidemicVEEreliesonacombinationofeco-
IEoccurfromBoliviatoMexico,andthecloselyrelatedEverglades logicandviralgeneticfactorsthatmustintersectintimeandspace.
virus(VEEcomplexsubtypeII)occursonlyinFlorida(Fig.4).Perma- Generally,theenzooticVEEVstrainsthatcirculatecontinuouslyare
nentorsemi-permanentzoonoticcyclesgenerallyincluderodents notcapableofequineamplificationbecausetheydonotproduce
as reservoir hosts and mosquito vectors in the subgenus Culex sufficient viremia. However, certain amino acid replacements in
(Melanoconion).Theseenzooticcyclesoccurinhumidtropicalfor- theE2envelopeglycoproteinthatformsthetipsofspikesonthe
estorswamphabitatsandtypicallygoundetected.Directspillover VEEVsurfacemediateenhancedequineamplification(Braultetal.,
tohumanshasbeendocumentedinseverallocationswhereactive 2002a).Becausethesereplacementscanresultfromasinglemuta-
casesurveillancecombinedwithlaboratorydiagnosticshasuncov- tionintheviralgenome(Anishchenkoetal.,2006),andbecause
eredextensivehumandisease,includingfatalcases(Aguilaretal., alphaviruses, like other RNA viruses, replicate with low genetic
2004;Johnsonetal.,1968;Quirozetal.,2009;Wattsetal.,1998, fidelity(Weaveretal.,1993),amplification-competentmutations
1997).TypicallyVEEcasesoverlapconsiderablyinsignsandsymp- probably occur regularly within sylvatic cycles where enzootic
toms with many acute, tropical febrile infectious diseases such strainsarefound.Selectionofthesemutationsundoubtedlytakes
as dengue fever (DEN), so cases undoubtedly are grossly under- place within equids, though it is also possible that some sort of
reported in locations where clinician awareness and laboratory intermediate host is also involved in the selection of epidemic
diagnosticsarelacking. strains.
Majorepidemicsoccurperiodicallyandsomewhatsporadically Geneticstudieshaveshownthatmostbutnotalloftheepidemic
whenVEEVstrainsemergewiththepotentialforamplificationin VEEV strains in subtypes IAB and IC also are more infectious for
equids.ThesestrainswithinsubtypesIABandICutilizemosquito theepidemicmosquitovector,Aedes(Ochlerotatus)taeniorhynchus,
vectorssuchasAedesandPsorophoraspp.,whichareabundantin thattypicallytransmitsamongequidsandhumansincoastalareas
agriculturalsettingsandcompetenttotransmitVEEVamongsus- (Braultetal.,2002b).TheexceptionisaICgenotypethatfailedto
ceptible horses, donkeys and mules. Because these amplification spreadintocoastalareasofVenezuelain1993,andthusproduced
hostsgeneratehightiteredviremias,extensiveVEEVcirculationin only a minor epidemic (Rico-Hesse et al., 1995). Strains isolated
agriculturalsettingsfrequentlyresultsinspillovertransmissionto fromthisoutbreakinefficientlyinfectedAe.taeniorhynchus,indicat-
humans.AswiththeenzooticVEEVstrains,epidemicstrainscausea ingthattheinabilityofthisgenotypetoadapttothiscriticalvector
336 S.C.Weaver,W.K.Reisen/AntiviralResearch85 (2010) 328–345
limiteditsspread(OrtizandWeaver,2004).Evenstrongerevidence Inadditiontotheriskoffutureequine-mediatedVEEepidemics,
oftheimportanceofVEEVadaptationtoepidemicvectorscomes thepossibilityofhuman-amplifiedtransmissionmustbeconsid-
from studies of recent Mexican epizootics. Unlike their closely ered (Table). Infected people develop high titered viremia after
relatedenzooticrelatives,whichpresumablyrepresenttheirances- infection with both enzootic (Aguilar et al., 2004; Quiroz et al.,
tors,VEEVstrainsfromtherecentoutbreaksefficientlyinfectAe. 2009) and epidemic (Bowen and Calisher, 1976; Weaver et al.,
taeniorhynchus.TherelativelyrecentadaptationoftheseMexican 1996) VEEV strains. Furthermore, urban, peridomestic mosquito
strainstothisimportantvector,coincidentwiththefirstepizootic vectorssuchasAedesaegypti(Ortizetal.,2008;SuarezandBergold,
emergenceintheregion,hasbeenlinkedtoasingleaminoacidsub- 1968)andAedesalbopictus(BeamanandTurell,1991;Fernandezet
stitutionintheE2proteinthatincreasesinfectionofthemosquito al., 2003; Turell and Beaman, 1992) are capable of transmission
midgut,againunderscoringthedramaticeffectsofsmallgenetic afteroraldosescomparabletohumanviremiatiters.Therefore,the
changesonarbovirusphenotypes(Braultetal.,2004). keyprerequisitesforurban,human-amplifiedVEEVtransmission
Phylogeneticstudiesindicatethatonlyoneofsixdifferentsub- wouldappeartobemet,because:(1)humanviremiaissufficientto
typeIDVEEVlineages,andnoneoftheIElineages,haveproduced infectperidomesticvectors;and(2)theseperidomesticmosquitoes
theepidemicsubtypeIABandICstrains(Powersetal.,1997).This havetheabilitytotransmitVEEV.ThepastepidemicVEEVtrans-
epidemic-progenitorlineageoccursinwesternVenezuela,Colom- missionnearmajorcitiessuchasMaracaibo,Venezuela(Weaveret
bia, and the Amazon areas of Ecuador and Peru. The failure of al.,1996),whereAe.aegyptireadilysupportsDENVtransmission,
the remaining ID lineages to generate epidemic strains, despite raisethequestionofwhytheseoutbreakshavenotsparkedurban
theiroccurrenceinlocationswheremajorepidemicshavespread, transmission.Furthermore,enzooticVEEVregularlyinfectspeople
suggeststhatgeneticconstraintsoftheenzooticstrainslimitthe inneotropicalcitieslikeIquitos,Peru,thatareincloseproximity
generationofequine-amplification-competentmutants. to forest habitats and that support epidemic DENV transmission
In addition to critical mutations, epidemic VEEV emergence (Rochaetal.,2009).ItmayjustbeamatteroftimebeforeanAe.
also depends on the transport of nascent equine-amplification- aegypti-borne epidemic VEEV cycle emerges, which would have
competent mutants to locations with susceptible equids and devastatingpublichealthconsequences.
mosquito vectors. Many equids that are pastured near forests
where enzootic VEEV circulates become infected and survive
4. Examplesofarboviralemergenceassociatedwith
with generally benign subtype ID and IE infections, generating
urbanization
a “halo” of immunity around enzootic foci. In addition, several
CulexmosquitoesinthesubgenusMelanoconionareenzooticvec-
4.1. Dengueviruses(DENV)
torsandgenerallynotcapableofepidemictransmissionbecause
they do not disperse far from their forest habitats (Mendez et
4.1.1. Distributionandhealthsignificance
al., 2001). Therefore, nascent epidemic strains probably must be
Denguevirusescomprisefourrelatedserotypesthatsharecom-
transported to locations distant from enzootic transmission foci
montransmissioncycles(Fig.5).Theyareflaviviruses(Flaviviridae:
where susceptible equids occur along with epidemic vectors in
Flavivirus)closelyrelatedtoJEVandWNVdescribedabove;how-
large numbers. The latter are generally floodwater or saltmarsh
ever,unlikeallotherflaviviruses,DENVsthatcausemosthuman
Aedes or Psorophora species that undergo population explosions
diseasearenotzoonoses,butexclusivelyutilizehumansasreser-
during unusually rainy seasons (Weaver et al., 2004). Another
voirandamplificationhosts.Alsounlikemostarboviruses,theyrely
enigmaconcerningVEEVemergenceiswhytheequine-virulentIAB
ontransmissionbymosquitovectorsthatliveincloseassociation
andICstrainsarenotmaintainedfollowingoutbreaks,i.e.emer-
withpeople;Ae.(Stegomyia)aegyptiistheprincipalvectorinmost
gence appears to be unidirectional. The most likely explanation
locations, with Ae. (Stegomyia) albopictus serving as a secondary
is that the mutations that adapt enzootic strains reduce the fit-
vectorinsomelocations(Table1).
nessofepidemicstrainsforenzootichostsorvectors.Experimental
DENVarethemostimportanthumanarboviralpathogens,with
infectionsofrodentreservoirhostssupportthishypothesis(SCW,
an estimated 50–100 million annual cases of DEN and tens-of-
unpublished).
thousandsofcasesofthemoresevereandsometimesfataldengue
hemorrhagic fever/shock syndrome (DHF/DSS syndromes) (Endy
3.5.3. Futuretrends
etal.,2010).Thelatterdiseasemanifestationswerefirstdescribed
ThelastmajorVEEepidemic,whichinvolvedca.100,000per-
afterWorldWarIIcoincidentwithincreasedurbanization,partic-
sons with an estimated 300 deaths, occurred in Venezuela and
ularlyinAsia.Today,DENishyperendemicinmanyAsiantropical
Colombia in 1995 (Rivas et al., 1997; Weaver et al., 1996). This
regions,where2ormoreserotypescirculateendemicallyandepi-
outbreakmayhavebeeninitiatedbytheaccidentalreleasefrom
demically. Although DENV was probably introduced periodically
alaboratoryofanisolatefromthe1962to1966epidemic(Brault
intotheAmericasbysailingshipssincethe17thcentury,theemer-
etal.,2001).Currentunderstandingofthemechanismsofepidemic
gence of hyperendemic DEN in the Western Hemisphere began
VEEVemergenceindicatethatnaturalemergencewilloccurperi-
later,duetoapartiallysuccessfulcampaigntoeradicateAe.aegypti
odically, so long as equine herd immunity is not maintained at
to control yellow fever. This campaign succeeded in most of the
adequatelevelsinVenezuelaandColombiabyvaccinationornat-
Americasfromthe1950stothe1970s,butwasthendiscontinued.
ural acquisition of immunity from enzootic exposure. Epidemics
Ae.aegyptiquicklyrecolonizednearlyalloftheNeotropicsandsub-
probablyhavenotarisenintheAmazonBasinofPeruandEcuador,
tropics,andtheinvasionofDENVfollowedsoonthereafter.In1985,
wheretheprogenitorlineageofsubtypeIDoccurs,becauseequid
Ae.albopictuswasintroducedintotheU.S.(Hawleyetal.,1987)and
populationstendtobelowintheseregions.Theriskofepidemic
BrazilfromAsia,providingasecondaryvectorforDENVtransmis-
emergencemaybeincreasingduetotheconversionoflargeareas
sionintheAmericas.ThisspecieswastheprimaryvectorofDENV
of tropical forest to ranching and other forms of agriculture in
duringarecentoutbreakinHawaii(Effleretal.,2005).
ColombiaandVenezuela.Thisdeforestationincreasestheecotonal
boundaries around enzootic habitats and may thereby enhance
opportunitiesforinfectionofbridgevectorsorhighlymobilehosts 4.1.2. Factorsassociatedwithemergence
such as birds or bats capable of transporting nascent epidemic AlthoughmostDENVstrainshavenovertebratehostsotherthan
strainstolocationsconducivetothegenerationofanequineampli- humans,ancestralDENVarerepresentedbyprimitivenonhuman
fiedcycle. primate-bornestrainsthatcontinuetocirculateintheforestsof
S.C.Weaver,W.K.Reisen/AntiviralResearch85 (2010) 328–345 337
Fig.5. PhylogenetictreeofDENVstrainsderivedfromcompleteopenreadingframesavailableintheGenBanklibrary.ThephylogenywasinferredusingBayesiananalysis
(onemillionreiterations)andallhorizontalbranchesarescaledaccordingtothenumberofsubstitutionspersite.Bayesianprobabilityvaluesareshownforkeynodes.Virus
strainsandbranchesarecoloredgreenforsylvatic(nonhumanprimateandarborealmosquitoisolates)andredforendemic(humanandperidomesticAedesisolates)and
strainscodedbyabbreviatedcountryofcollection/strainname/yearofcollection.DashedgreenlineindicateshypotheticalsylvaticDENV-3lineagesuggestedbynonhuman
primateseroconversionsinMalaysia(Rudnick,1978).
Table1
Characteristicsofarboviruseswiththeriskofurbanization.
Virus Historyoftemporary Historyofpermanent Humanviremiasuitable Experimental Mutationsassociated References
urbanizationa urbanizationa forvectortransmissionb competenceofurban withurbanemergence
vectorsb
DENV Yes Yes Yes Yes No(exceptAsianstrains VasilakisandWeaver
ofDENV-2;seeFig.5) (2008)
CHIKV Yes Yes Yes Yes E1envelopeglycoprotein Schuffeneckeretal.
mutationenhancesAe. (2006),Tsetsarkinetal.
albopictusinfection (2007),Vazeilleetal.
(2007)
YFV Yes No Yes Yes No Monath(2001)
ZIKV Yes No Yes(presumedbasedon No(butisolationfromAe. No Duffyetal.(2009),
Yapoutbreak) aegypti) Marchetteetal.(1969)
VEEV No No Yes Yes No(althoughE2 Anishchenkoetal.
envelopeglycoprotein (2006),Braultetal.
mutationsenhance (2002a,2004),Weaveret
infectionofepidemic al.(2004)
vectorsandequine
amplificationhosts)
MAYV No No Unknown Yes No Teshetal.(1999),Aguilar
andWeaver
(unpublished)
a Urbantransmissionexceeding5yearsisconsideredpermanent.
b Aedesaegyptiand/orAe.albopictus.