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Abiotic

and

biotic

factors

affecting

the

replication

and

pathogenicity

of

bee

viruses

Alexander

J

McMenamin

1,4

,

Laura

M

Brutscher

1,4

,

William

Glenny

1,3

and

Michelle

L

Flenniken

1,2,4

Beesareimportantpollinatorsofplantsinbothagriculturaland

non-agriculturallandscapes.Recentlossesofbothmanaged

andwildbeespecieshavenegativeimpactsoncrop

productionandecosystemdiversity.Therefore,inorderto

mitigatebeelosses,itisimportanttoidentifythefactorsmost

responsible.Multiplefactorsincludingpathogens,

agrochemicalexposure,lackofqualityforage,andreduced

habitataffectbeehealth.Pathogenprevalenceisonefactor

thathasbeenassociatedwithcolonylosses.Numerous

pathogensinfectbeesincludingfungi,protists,bacteria,and

viruses,themajorityofwhichareRNAvirusesincludingseveral

thatinfectmultiplebeespecies.RNAvirusesreadilyinfect

bees,yetthereislimitedunderstandingoftheirimpactsonbee

health,particularlyinthecontextofotherstressors.Hereinwe

reviewtheinfluenceenvironmentalfactorshaveonthe

replicationandpathogenicityofbeevirusesandidentify

researchareasthatrequirefurtherinvestigation.

Addresses

1DepartmentofPlantSciencesandPlantPathology,MontanaState University,Bozeman,MT,USA

2

InstituteonEcosystems,MontanaStateUniversity,Bozeman,MT,USA 3DepartmentofEcology,MontanaStateUniversity,Bozeman,MT,USA 4DepartmentofMicrobiologyandImmunology,MontanaState University,Bozeman,MT,USA

Correspondingauthor:Flenniken,MichelleL (michelle.flenniken@montana.edu)

Current Opinion in Insect Science 2016,16:14–21

ThisreviewcomesfromathemedissueonVectors and medical and veterinary entomology

EditedbyZach N Adelman andKevin Myles ForacompleteoverviewseetheIssue andtheEditorial Availableonline26thApril2016

http://dx.doi.org/10.1016/j.cois.2016.04.009

2214-5745/# 2016TheAuthors.PublishedbyElsevierInc.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creative-commons.org/licenses/by-nc-nd/4.0/).

Introduction

Honeybees(Apismellifera),bumblebees(Bombusspp.),and otherinsectsplayavitalroleinecosystemsasplant polli-nators.The annualestimatedvalue of crops directly de-pendentoninsectpollinationworldwideis$175billion[1] andapproximately$17-18billionin both North America

andtheEuropeanUnion[2,3].Wild,native,andmanaged bee species perform the majority of pollination services inbothagriculturalandnon-agriculturallandscapes. Bum-blebees are the primary pollinators of somecrops (e.g., tomatoes)andaugmentpollinationof othercrops [4].In large-scale crop (e.g.,almond, apple, cherry) production honeybeesarethe primarypollinators,sincetheyforage overlargedistancesandcanbemaintainedintransportable hives.HoneybeeswereintroducedtoNorthAmericainthe early 1600s as a managed species kept by beekeepers primarily for honey production [5]. Today, the majority ofUShoneybeecolonies aremaintainedbycommercial beekeepingoperations.Coloniesmanaged bysmall-scale beekeepersandferal(orunmanaged)coloniesmakeupthe remainingpopulation.

Highannuallossesofmanagedhoneybeesandpopulation declinesofwildbumblebeesareofgreatconcernsincebee pollinatorsareimportantforplantreproductionandcrop production[6,7,8].InsomeregionsoftheUS,bumblebees haveexperiencedbetween23%and86%rangereduction [7,8] and annual losses of US honey bee colonies have averaged33%since2006(reviewedin[9]).Severalstudies havefocusedonassessingtherelationshipbetweencolony healthandtheeffectsofmultiplebiotic(e.g.,pathogens, beegenetics,andqueenlongevity)andabioticfactors(e.g., agrochemical exposure, weather,and management prac-tices)[7,10,11,12,13,14].Thesestudiesindicatethat patho-gens,agrochemicalexposure,andlackofqualityforageand habitatallcontributeto beelosses,thoughinvestigating therelativeroleofthesefactorsisanactiveareaofresearch. Pathogens, including the microsporidia Nosema ceranae, trypanosomatids,viruses,andtheectoparasiticmiteVarroa destructor, contribute to honey bee colony losses [15,16,17,18,19,20,21,22,23,24,25] (reviewed in [11,26,27,28,29]),andthemicrosporidiaNosemabombiis associatedwithdecliningbumblebeepopulationsinthe US[7,8].

The largestclass of honey bee infecting pathogens are positive-sense single stranded RNA viruses including: Acutebeeparalysisvirus(ABPV),Blackqueencellvirus (BQCV),Israeliacutebeeparalysisvirus(IAPV),Kashmir beevirus(KBV),Deformedwingvirus(DWV),Kakugo virus(KV),Varroadestructorvirus-1(VDV-1),Sacbrood virus (SBV), Slow bee paralysis virus (SBPV), Cloudy wingvirus(CWV),BigSiouxRivervirus(BSRV),Aphid lethalparalysisvirus(strainBrookings)(ALPV),Chronic beeparalysisvirus(CBPV)(reviewedin[15,17,28]),the

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LakeSinaiviruses(LSV)[21],andBeemacula-likevirus (BeeMLV)[30].Inaddition,onedouble-strandedDNA virus, Apismelliferafilamentousvirus(AmFv)hasbeen isolated from honey bees [31]. The majority of bee-infecting viruseswereoriginally discovered and charac-terized in honey bees, likely since they are the most investigated species.Detectionofthesevirusesin other arthropods indicates that origin of discovery does not necessarily reflect host-range, host–pathogen evolution, ordirectionalityofinter-speciestransmission(i.e.,ABPV, IAPV, DWV, BQCV, SBV, SBPV, LSV and VdMLV) [32,33,34,35,36,37]. Bee viruses are transmitted both verticallyand horizontally[38],includingbetween and among co-foraging wild and managed bee popula-tions[32,39,40].VirusesarealsotransmittedbyVarroa destructormites,whichalsosupportreplicationofasubset oftheseviruses[41,42,43,44].Honeybeevirusinfections maycausedeformities,paralysis,death,orremain asymp-tomatic[15].Theseverityofvirusinfectionisinfluenced by numerous factors that impact bee health, including genetic composition of both host and virus, immune response, synergistic and/or antagonistic pathogenic infections, microbial composition, nutritional status, and agrochemical exposure [15,27,28,45,46,47]. The focus of this review is to highlight recent studies on theabioticandbioticfactorsthataffectbeevirus replica-tionand pathogenicity.

Bee

health,

nutrition,

habitat,

and

colony

management

Bees obtainnutrients from nectar and pollen,and ade-quate nutritionis important for proper immune system function(reviewedin[48]).Thoughtherehavebeenfew quantitative assessments of the relationship between nutritional status and pathogen burden ([49] and reviewedin[47]),severalstudiessuggestthatinsufficient protein and low-diversity dietsnegatively impact bees’ abilitytodefendagainstpathogens[49,50,51].In labo-ratory-basedstudies,naturallyDWV-infectedhoneybees that werefed aprotein-freesucrose-syrup diethad sig-nificantlyhigherDWVlevelscomparedtobeesfedeither pollen or a protein-supplement [50]. Intriguingly, the pollen-fed group had reduced DWV virus load by day four of the trial, whereas the protein supplement fed group exhibited reduced virus load several days later [50].Whileanadequateamountof proteinisimportant, adiversepollendiet,asopposedtomonofloralpollenor additional protein, enhanced adult bee immunocompe-tence(i.e.,haemocyteconcentration,fatbodymass, and phenoloxidaseandglucoseoxidaseactivities)[49]. To-getherthesestudiessuggestthatwhileproteinis impor-tant, thesource ofthis protein is alsocritical to proper immunefunction.Similarly,beesfedhoney,which con-sists of30–45%fructose, 24–40% glucose,0.1–4.8% dis-accharides including sucrose, and minute amounts of micronutrients and amino acids, exhibited increased expression in more genes involved in detoxification,

immunity, aromatic amino acid metabolism,and oxida-tionandreduction,ascomparedtobeesfedeithersucrose or high fructose corn syrup [51,52]. Together, these studiesindicatethatpropernutrition(i.e.,adequate pro-tein and carbohydrates) and natural and diverse food sources (i.e., nectar and pollen) enhance bee immune function.However,themechanismsandgeneregulatory pathwaysinvolvedinnutrition-dependent immunocom-petencerequire furthercharacterization.Future studies should employbothcage-studies,whichprovidea well-controlled environment to investigate individual bee responsesand facilitatestandardizationofmultiple vari-ables (e.g., pathogen dose), andcolony levelstudies. A more thoroughunderstandingof theroleof dietonbee health is important, as it is commonfor beekeepers to provide supplemental feed when natural sources are scarce. Overall, these studies indicate that managing landscapes to enhance floral, and therefore nutritional diversitywillbenefitthehealthofbothmanagedandwild beepopulations.

Whilefloralresourcesareessentialtobeehealth,flowers also serve asa hubfor pathogentransmissionand agro-chemicalexposure[32,33,40].Themostwell docu-mented intra- and inter-species transmissible bee pathogens are RNA viruses [32,33,39,53,54,55]. Transmissionofthesevirusesisthoughttobeassociated with bee foraging activities, as BQCV, SBV, and DWV have been detected in honey bee collected pollen [32,40]. In addition, inter-species transmission was demonstrated experimentally in greenhouse studies in whichIAPVwastransmittedfromhoneybeestobumble beesandviceversa[32].Phylogeneticanalysesofvirus genome sequences (i.e., BQCV, DWV, and IAPV) obtained from foraging honey bees,pollen pellets, and non-Apis hymenopteran, including solitary bees, wasps, and bumble bees, did not cluster by host, providing further evidence of inter-speciestransmission[32]. In addition, IAPVwasdetectedinnon-Apishymenopteran species collected from sites near IAPV-infected honey beecolonies,whereaswildhymenopteransobtainedfrom areasproximaltohoneybeesthatwerenotinfectedwith IAPV werealso IAPV-negative [32].Likewise, recent evaluationofthevirusesassociatedwithsympatrichoney beeandbumblebeepopulationsinGreatBritainandthe Isle of Man indicated they were infected with similar strainsofDWVandVDV[39],andBQCV,DWV,ABPV, SBPV, and SBVweredetectedin both honeybeesand bumble bees in thesame geographic area, thoughviral prevalenceandabundancevariedbyspecies[33].Based onmodelingdata,itwassuggestedthatthedirectionality of DWV transmission was from honey bees to bumble bees, since DWV was more prevalent and abundant in honeybeesthaninbumblebeeswhererangesoverlapped [39].ThisrelationshipwasreversedforABPVandSBV, whichweremoreprevalentinbumblebeesthaninhoney bees where ranges overlapped [33]. Although viruses

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aresharedbetweenhoneybeesand bumblebees,there havebeenveryfewstudiesthathaveinvestigatedtherole of viruses on bumble bee health, as most efforts have focusedontheroleof eukaryoticpathogensonbumble bee health [53,56,57,58,59]. Additional epidemiologic studiesarerequiredtobetterunderstandpathogen trans-mission between and within wild and managed bee populations, since the dynamics of transmission will likelyvaryacrossdifferentgeographiesandbeinfluenced bythelocalabundanceof particularbeespecies, patho-genprevalence,andanthropogenicfactorsincludingland use[48,60]andagrochemicalexposure[61,62]. Prox-imitytourbanizationandcolonymanagementhavebeen linked to increased pathogen pressure on honey bees [60]. A study of feral and non-commercially managed honeybeecoloniesacrossanurbanizationgradient deter-minedthatferalbeesweremoreimmunocompetent (as indicatedbyapproximatelytwo-foldincreasedexpression of four immune genes after challenge) than managed bees,thaturbanizationpositivelycorrelatedwithgreater

NosemaceranaeandBQCVprevalence,andthat manage-mentwaspositivelycorrelatedwithhigherprevalenceof bothNosemaapis andNosemaceranae [60].

Impact

of

agrochemical

exposure

on

virus

replication

and

pathogenesis

Bee health isinfluenced bya variety of environmental factorsincludingexposureto agrochemicals. Agrochem-icals,includingpesticides,herbicides,andfungicidesare usedwidelyacrossarangeoflandscapes(e.g., agricultur-al, non-agricultural, wild, managed, and residential), as wellaswithinmanagedhoneybeecolonies. Agrochemi-calexposuresometimesresultsinacutebeelosses,aswell as sublethal toxicity, therefore there is much concern regarding the role of pesticides, particularly neonicoti-noids, in bee declines (reviewed in [62,63,64]). Although, the latest insecticide formulations may pose less of a threat to bee health as compared to previous formulations [62,64,65]. Compared to other insects, honeybeeshaveareduced repertoireofgenesinvolved indetoxification[66],andatleastonestudyindicatedthat bees prefer neonicotinoid-containing food [67]; these studiesunderscoretheimportanceoffurther examining the risks associated with agrochemical exposure. Many studieshavefoundthatinsecticides,including neonico-tinoids, negatively impact bee health ([18,68,69,70, 71,72,73,74,75,76] and reviewed in [62]).However, several studies determined that typical field exposure levels are below known toxicity thresholds [77,78,79]; specifically,oraladministration of imidaclopridat5ppb [77,78] or contactwith thiacloprid atdosesbelow 6mg/ bee (approximately 50ppm) [80] had no observable negativeimpact.

Themajorityofstudiesinvestigatingtheeffectsof agro-chemicalsonbeehealthhavefocusedonneonicotinoids (reviewed in [62]). Several studies suggest that

exposure to these chemicals increases pathogen abun-dance[18,76,81].Specifically,fullsizedhoneybee colo-nies exposed to imidacloprid (2 or 20ppb in pollen patties)had greaterlevelsof Nosemaceranae than unex-posedcolonies [18].Likewise,exposingbees to imida-clopridandclothianidintopically(0,10,20,and30ngper bee, which corresponds to approximately 83, 167, and 450ppm)and orally (0.1, 1.0, and10ppb)resulted in a dose-dependentincreaseofDWVlevels[73].Similarly, sublethal,thoughnotnecessarilyfield-relevant,dosesof thiacloprid(0.1ppminlarvalfood)increasedBQCVtiters andlarvalmortality[76].Thisindicatesthatagrochemical exposureand viralinfectionsynergisticallyharm larvae, thoughnegativeimpactswerenotobservedinadults[76].

There are numerous other (non-neonicotinoid) agro-chemicals that are utilized in both agricultural and non-agriculturalsettingsthathavereceivedlessattention andscientificinvestigation[82],thoughtheymayimpact pathogen abundance and bee health. Chlorpyrifos, an organophosphate,and Pristine1, a fungicide composed ofboscalidandpyraclostrobinusedduringalmondbloom, negativelyaffected queenhealth [70]. Chlorpyrifos de-creased queen emergence and increased DWV abun-dance, but not prevalence, in queens relative to the nurse bees tending them [70]. Colonies treated with chlorpyrifos and Pristine1 had decreased queen emer-gence,butviralprevalenceorabundancewasnotaffected relative to chlorpyrifos alone [47]. In contrast, reduced queenemergencewasnotfoundwhencoloniesin isolat-edswarmboxeswerefedpollentreatedwithPristine1or Pristine1withanadjuvant,whereascoloniestreatedwith diflubenzuron, aninsect growthregulator, had a signifi-cantreductiononqueensurvival [83].

Inadditiontoagrochemicalexposurefromforaging(i.e., nectarandpollen)andviafoodsources(i.e.,beebreadand royaljelly),honeybeesarealsoexposedtoagrochemicals withinthecolony (e.g., antibioticsand miticides). Bee-keepersroutinelyutilizethefungicideFumagillan-B1to reduce levels of Nosema apis and Nosema ceranae, and acaricides(e.g.,tau-fluvalinate,thymol,coumaphos, for-mic acid, and amitraz) to reduce Varroa destructor mite infestation[61,84].WhileVarroa isoneofmanybiotic factors contributing to colony losses [85], high Varroa

levels, above the threshold of >3 mites per 100 bees [86], are associated with increased pathogen load [17,87,88](reviewedin[89]).Furthermore,mitesserve asamechanismforpathogentransmissionbetween colo-nies (reviewed in [90]). Unfortunately, some research suggeststhatacaricidesmayreducehoneybee immuno-competence [91]. Bees with compromised immune responseswouldbeexpectedtoharborgreaterpathogen loads, though acaricide treated bees exhibited variable levelsofpathogens[88,91].Incontrast,acaricide treat-mentdidnotaffectpathogenloads incolonieswith low mitepressure[91].However,beesobtainedfromcolonies

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thatweretreatedwiththymolandcoumaphosexhibited significantly reduced expression of two immune genes (DSC37 and BASK) [91]. Interestingly, tau-fluvalinate application resulted in increased DWV levels in adult honey bees and Varroa, BQCV in mite-infested pupae, andSBVinpupaenotinfestedwithmites[88]. Impor-tantly,tau-fluvalinatetreatedcoloniesshowedlong-term reduction in DWVandDWV-associatedsymptoms, and thusdemonstratedthatproperacaricideuseisimportant, andmaybeeffectiveincontrollingDWVlevels[88].The relationshipsbetweenmitelevels,acaricideexposure,viral abundance,andbeeimmunegeneexpressionarecomplex andvariable.However,inonestudy,increasedexpression ofhoneybeeimmunegenes(relish,PGRP-S1, hymenoptae-cin, apidaecin, defensin, and PPOAct) correspondedto de-creased mitereproduction[92].Inaddition,thisstudy foundnoevidencethatVarroanegativelyimpactedhoney beeimmunocompetence[92].Themajorityofcolonies inNorthAmericaareinfestedwithVarroamites[90]and mostmanagedhoneybeesinNorthAmericaare continu-ously exposed to acaricides in wax [61]. Therefore, a better understandingof theimpactofthesestressors on beehealthisanimportantareaofongoingresearch. For many agrochemical formulations a lethal dose 50 (LD50) and/or exposure threshold for bees at various

stagesofdevelopmentisnotknownandevenless infor-mation is available regarding synergistic interactions of thesechemicalsinbees[62,93,94].Regardless,research and public opinionhave resulted in bans ontheuse of clothianidin,thiamethoxam,andimidaclopridintheEU [95]andhaveresultedinadditionalUSEPAregulations on new registrations for neonicotinoids [96]. The evi-dence to date suggests that bee colony losses are not solely dependent upon agrochemicals, but are likely a resultofacombinationoffactors.Agrochemicalscanpose problems, but they are often required for large-scale production ofagriculturalcrops,and theirproper useas part of an integrated pest management strategy (IPM) often results in low to no levels of exposure in field settings[77,78,79].Thesestudiesandincreased prophy-lactic usageofneonicotinoids(i.e.,as treatedseedswith nootherpurchaseoptions),underscoretheimportanceof continuedresearchontheeffectsofagrochemicalsonbee health.Inaddition,lossofforageduetoherbicideusein manylandscapesimpactstheavailabilityofqualityforage for allbeespecies(reviewedin[78]).

Bee

microbiome

Bee-associatedmicrobesarenotlimitedtopathogens,but also includecommensalmicrobes ([97,98]and reviewed in[46]).Thebestcharacterizedcommensalmicrobesof bees are honey bee gut associated bacteria, including eight bacterial phylotypespredominantly in the Proteo-bacteria,Firmicutes,andActinobacteriaphyla([99,100]and reviewed in [46]). The relationship between the gut microbiome and viruses has been characterized in

mammals (reviewed in [101]) and in solitary insects, including fruit flies and mosquitoes. In fruit flies and mosquito spp., several strains of the bacteria Wolbachia

reduceRNAvirusreplicationandplasmodiuminfection [102,103]. Wolbachia 16S rRNA sequences have been detectedindifferentsubspeciesofApismelliferasamples fromsouthernAfrica[104]andGermany[105],andinfive speciesofEuropeanbumblebees[110],butthepotential influenceofWolbachiaonvirusinfectionsinbeeshasnot been studied.Recent findingssuggest that Parasacchar-ibacter apiumin may improve larval survival [106], and enhancedefenseagainstNosema[107],but thepotential effectsofthisbacteriaonvirusreplicationisnotknown. Bee microbiome research has primarily focused on the benefitsofthesemicrobestobeehealth,butnotall bee-associatedbacteriaarebeneficial;somemaybe opportu-nistic pathogens (e.g., F. perrara) [108,109], whereas others(i.e.,PaenibacilluslarvaeandMelissococcusplutonius) are pathogenic.The relationshipbetween thebee bac-teriomeandvirome,aswellastheeffectsofbothonbee healthrequirefurthercharacterization.

Summary

Beepollinatorsinhabitarangeofenvironmentsincluding wild,agricultural,andurbanlandscapes.Inthesediverse settings, multiple factors including pathogens, nutrient availability,agrochemicalexposure,andthemicrobiome converge to affectbee health. Thesefactors affectbee immunocompetence and virusreplication and pathoge-nicity. Furthermore, land and pollinator management practicesimpact beehealthandmayresultin increased pathogenpressureonbees.Managinglandscapesto en-hance floral diversity will benefit the health of both commercial and wild bee populations. Floral resources arenotonlyimportanttobeehealth,butalsoserveassites of pathogen transmission and agrochemical exposure. Agrochemicals, including those used within honey bee colonies, seem to impact disease severity, though the processes involved require further elucidation. Lastly, theemergingfieldofinsectmicrobiomeresearchpresents exciting avenues of inquiry, including how the bacter-iomeandviromeinteractatthehost-level.Better under-standing of bee biology, the factors that influence bee health,pathogentransmission,andimmunemechanisms willresultinthedevelopmentof managementpractices thatsupportpollinatorhealth.

Conflict

of

interests

The authors declare thatthere isnoconflictof interest regardingthepublicationof thispaper.

Acknowledgements

TheFlennikenLaboratoryissupportedbytheUnitedStatesDepartment ofAgricultureNationalInstituteofFoodandAgriculture,Agricultureand FoodResearchInitiative(USDA-NIFA-AFRI)Program,Montana DepartmentofAgricultureSpecialtyCropBlockGrantProgram,the NationalInstitutesofHealthIDeAProgramCOBREgrantGM110732, NationalScienceFoundationEPSCoRNSF-IIA-1443108,HatchMultistate

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Funding(NC-1173),ProjectApism.,theMontanaStateBeekeepers Association,MontanaStateUniversity,andtheMontanaStateUniversity AgriculturalExperimentStation.LauraM.Brutscherissupportedbythe ProjectApism.-CostcoHoneyBeeBiologyFellowship.Wewouldliketo thankmembersoftheFlennikenlaboratory(KatieDaughenbaugh,Emma Garcia,JennaSeverson,CayleyFaurot-Daniels,andElisaBoyd)for reviewingthismanuscriptpriortopublication.

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Thisreviewprovidesacomprehensiveoverviewofhoneybeeantiviral defensemechanisms.

29. vanEngelsdorpD,TarpyDR,LengerichEJ,PettisJS:Idiopathic brooddiseasesyndromeandqueeneventsasprecursorsof colonymortalityinmigratorybeekeepingoperationsinthe easternUnitedStates.PrevVetMed2013,108:225-233. 30. deMirandaJR,CornmanRS,EvansJD,SembergE,HaddadN,

NeumannP,GauthierL:Genomecharacterization,prevalence anddistributionofamacula-likevirusfromApismelliferaand Varroadestructor.Viruses2015,7:3586-3602.

31. GauthierL,CornmanS,HartmannU,CousseransF,EvansJD,de MirandaJR,NeumannP:TheApismelliferafilamentousvirus genome.Viruses2015,7:3798-3815.

32.

SinghR,LevittAL,RajotteEG,HolmesEC,OstiguyN, vanEngelsdorpD,LipkinWI,DepamphilisCW,TothAL, Cox-FosterDL:RNAvirusesinhymenopteranpollinators:evidence ofinter-Taxavirustransmissionviapollenandpotential impactonnon-Apishymenopteranspecies.PLoSONE2010, 5:e14357.

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ThispaperpresentedsomeofthefirstevidencethatRNAvirusesinfect multiplebeespeciesinnaturalsystemsanddemonstratedinter-species transmission between honey bees and bumble bees in greenhouse studies.

33.

McMahonDP,Fu¨rstMA,CasparJ,TheodorouP,BrownMJF, PaxtonRJ:Astinginthespit:widespreadcross-infectionof multipleRNAvirusesacrosswildandmanagedbees.JAnim Ecol2015http://dx.doi.org/10.1111/1365-2656.12345.

Thisstudywasoneofthefirstlarge-scaleepidemiologicalsurveysof virusesco-occurringinsympatrichoneybeeandbumblebeepopulations intheUK.

34. LevittAL,SinghR,Cox-FosterDL,RajotteE,HooverK,OstiguyN, HolmesEC:Cross-speciestransmissionofhoneybeeviruses inassociatedarthropods.VirusRes2013,176:232-240. 35.

LiJ,PengW,WuJ,StrangeJP,BoncristianiH,ChenY: Cross-speciesinfectionofdeformedwingvirusposesanewthreatto pollinatorconservation.JEconEntomol2011,104:732-739. Thiswasoneofthefirststudiestoexaminetissue-specificDWVlevels andreplicationinfieldcollectedbumblebees.

36. PengW,LiJ,BoncristianiH,StrangeJP,HamiltonM,ChenY: HostrangeexpansionofhoneybeeBlackQueenCellVirusin thebumblebee,Bombushuntii.Apidologie2011,42:650-658. 37.

ParmentierL,SmaggheG,deGraafDC,MeeusI:Varroa destructorMacula-likevirus,LakeSinaivirusandothernew RNAvirusesinwildbumblebeehosts(Bombuspascuorum, BombuslapidariusandBombuspratorum).JInvertebrPathol 2015http://dx.doi.org/10.1016/j.jip.2015.12.003.

ThisstudywasthefirsttosurveythepresenceofVMLV,LSV,andother RNAvirusesinthreewildbumblebeespecies.Furthermore,they deter-minedthatpopulationsnearapiariesweremorelikelytobeinfected,and thatLSVinfectionmayeitherincreasethelikelihoodofasecondinfection orbeapredictorofco-infection.

38. ChenYP,PettisJS,CollinsA,FeldlauferMF:Prevalenceand transmissionofhoneybeeviruses.ApplEnvironMicrobiol2006, 72:606-611.

39. Fu¨rstMA,McMahonDP,OsborneJL,PaxtonRJ,BrownMJF: Diseaseassociationsbetweenhoneybeesandbumblebeesas athreattowildpollinators.Nature2014,506:364-366. 40.

MazzeiM,CarrozzaML,LuisiE,ForzanM,GiustiM,SagonaS, TolariF,FelicioliA:InfectivityofDWVassociatedtoflower pollen:experimentalevidenceofahorizontaltransmission route.PLoSONE2014,9:e113448.

This study presented evidence that field-collected pollen contained infectiveDWV,andthatthesolitarybeeOsmiacornutacanserveasa DWVhost.

41. deMirandaJR,DainatB,LockeB,CordoniG,BerthoudH, GauthierL,NeumannP,BudgeGE,BallBV,StoltzDB:Genetic characterizationofslowbeeparalysisvirusofthehoneybee (ApismelliferaL.).JGenVirol2010,91:2524-2530.

42. BoncristianiHF,DiPriscoG,PettisJS(null),HamiltonM,ChenYP: Molecularapproachestotheanalysisofdeformedwingvirus replicationandpathogenesisinthehoneybee,Apismellifera. VirolJ2009,6:221.

43. ChenY,PettisJ,EvansJ,KramerM,FedlauferM:Transmission ofKashmirbeevirusbytheectoparasiticmiteVarroa destructor.Apidologie2004,35:441-448.

44. ShenM,CuiL,OstiguyN,Cox-FosterD:Intricatetransmission routesandinteractionsbetweenpicorna-likeviruses(Kashmir beevirusandsacbroodvirus)withthehoneybeehostandthe parasiticvarroamite.JGenVirol2005,86:2281-2289. 45.

MartinSJ, Highfield AC,Brettell L,VillalobosEM,BudgeGE, PowellM, NikaidoS,SchroederDC:Globalhoneybeevirallandscape alteredbyaparasiticmite.Science2012,336:1304-1306. This paper showed evidence that the viral vector Varroa destructor influencedDWVstrainprevalenceinhoneybees.

46.

MoranNA:Genomicsofthehoneybeemicrobiome.CurrOpin InsectSci2015,10:22-28.

Excellentreviewofthehoneybeemicrobiomeresearch.

47. DeGrandi-HoffmanG,ChenY:Nutrition,immunityandviral infectionsinhoneybees.CurrOpinInsectSci2015,10:170-176.

48. VaudoAD,TookerJF,GrozingerCM,PatchHM:Beenutrition andfloralresourcerestoration.CurrOpinInsectSci2015, 10:133-141.

Thispaperisagreatreviewofbeenutritionalrequirementsandsuggests howtousethisknowledgeinhabitatrestoration.

49.

AlauxC,DuclozF,CrauserD,LeConteY:Dieteffectson honeybeeimmunocompetence.BiolLett2010,6:562-565. Thisstudydemonstratedthatbeehealthisimprovedbydietsthatinclude diversepollensources;beesfedmonofloralpollensourceshadreduced levelsofimmunegeneexpression,ascomparedtobeesfedpollenfrom multiplesources.

50. DeGrandi-HoffmanG,ChenY,HuangE,HuangMH:Theeffectof dietonproteinconcentration,hypopharyngealgland developmentandvirusloadinworkerhoneybees(Apis melliferaL.).JInsectPhysiol2010,56:1184-1191.

51. WheelerMM,RobinsonGE:Diet-dependentgeneexpressionin honeybees:honeyvs.sucroseorhighfructosecornsyrup.Sci Rep2014,4:5726.

Thisstudyexaminedtheeffectofdietongeneexpressionandprovideda basisforunderstandingthemechanismsofnutritionalfactorsonhost physiology.

52. MaoW,SchulerMA,BerenbaumMR:Honey constituents up-regulate detoxification and immunity genes in the western honey bee Apismellifera.ProcNatlAcadSciUSA2013http:// dx.doi.org/10.1073/pnas.1303884110.

53.

GraystockP,MeeusI,SmaggheG,GoulsonD,HughesWOH:The effectsofsingleandmixedinfectionsofApicystisbombiand deformedwingvirusinBombusterrestris.Parasitology2015 http://dx.doi.org/10.1017/S0031182015001614.

Thisstudyexaminedthepathophysiologicaleffectsofmixedinfectionin bumblebees.

54. GenerschE,YueC,FriesI,deMirandaJR:Detectionof Deformedwingvirus,ahoneybeeviralpathogen,inbumble bees(BombusterrestrisandBombuspascuorum)withwing deformities.JInvertebrPathol2006,91:61-63.

55.

RavoetJ,DeSmetL,MeeusI,SmaggheG,WenseleersT,de GraafDC:Widespreadoccurrenceofhoneybeepathogensin solitarybees.JInvertebrPathol2014,122:55-58.

ThisstudyexaminedpathogenoccurrenceinEuropeansolitarybees,and wasthefirsttoreportdetectionpathogensthatwerepreviouslyprimarily associatedwithhoneybeesinsolitarybeespecies.

56. CollaSR,OtterstatterMC,GegearRJ,ThomsonJD:Plightofthe bumblebee:pathogenspilloverfromcommercialtowild populations.BiolConserv2006,129:461-467.

57. BarribeauSM,Schmid-HempelP:Qualitativelydifferent immuneresponseofthebumblebeehost,Bombusterrestris, toinfectionbydifferentgenotypesofthetrypanosomegut parasite,Crithidiabombi.InfectGenetEvol2013,20:249-256. 58. ManleyR,BootsM,WilfertL:Emerging viral disease risk to

pollinating insects: ecological, evolutionary and anthropogenic factors.JApplEcol2015http://dx.doi.org/ 10.1111/1365-2664.12385.

59. OtterstatterMC,ThomsonJD:Doespathogenspilloverfrom commerciallyrearedbumblebeesthreatenwildpollinators? PLoSONE2008,3:e2771.

60.

YoungsteadtE,ApplerRH,Lo´pez-UribeMM,TarpyDR,FrankSD: Urbanizationincreasespathogenpressureonferaland managedhoneybees.PLoSONE2015,10:e0142031.

Thisstudyprovidedimportantinformationoftheeffectsofurban land-scapesandmanagementonbeeimmunocompetence.

61.

MullinCA,FrazierM,FrazierJL,AshcraftS,SimondsR, vanEngelsdorpD,PettisJS:Highlevelsofmiticidesand agrochemicalsinNorthAmericanapiaries:implicationsfor honeybeehealth.PLoSONE2010,5:e9754.

Thisstudywasthefirstcomprehensiveexaminationoftheagrochemicals associated with North American honey bee colonies; they reported frequentdetectionofnumerouschemicalsassociatedwithbeecolonies.

62.

JohnsonRM:Honey bee toxicology.AnnuRevEntomol2014 http://dx.doi.org/10.1146/annurev-ento-011613-162005.

Thisisacomprehensivereviewoftheaffectsoftoxinsonbees,including phytochemicalsandagrochemicals.

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63. JohnsonRM,EllisMD,MullinCA,FrazierM:Pesticidesand honeybeetoxicity—USA.Apidologie2010,41:312-331. 64. KrupkeCH,LongEY:Intersectionsbetweenneonicotinoid

seedtreatmentsandhoneybees.CurrOpinInsectSci2015, 10:8-13.

65. HardstoneMC,ScottJG:IsApismelliferamoresensitiveto insecticidesthanotherinsects? PestManageSci2010http:// dx.doi.org/10.1002/ps.2001.

66. BerenbaumMR,JohnsonRM:Xenobioticdetoxification pathwaysinhoneybees.CurrOpinInsectSci2015. 67.

KesslerSC,TiedekenEJ,SimcockKL,DerveauS,MitchellJ, SoftleyS,StoutJC,WrightGA:Beespreferfoodscontaining neonicotinoidpesticides.Nature2015,521:74-76.

Thisstudydemonstratedthatbeespreferneonicotinoidcontaminated foodsourcesand,thus,emphasizedtheneedfor additionalresearch focusedondeterminingtheaffectsoftheseandotheragrochemicalon beehealth,particularlythepotentialsublethalandbehavioraleffects. 68. WuJY,SmartMD,AnelliCM,SheppardWS:Honeybees

(Apismellifera)rearedinbroodcombscontaininghighlevels ofpesticideresiduesexhibitincreasedsusceptibilityto Nosema(Microsporidia)infection.JInvertebrPathol2012, 109:326-329.

69.

WuJY,AnelliCM,SheppardWS:Sub-lethaleffectsofpesticide residuesinbroodcombonworkerhoneybee(Apismellifera) developmentandlongevity.PLoSONE2011,6:e14720. Thisstudydemonstratedthatworkerbeesexposedtopesticide con-taminationexperiencednegativesublethaleffects.

70. DeGrandi-HoffmanG,ChenY,SimondsR:Theeffectsof pesticidesonqueenrearingandvirustitersinhoneybees (ApismelliferaL.).Insects2013,3:601-615.

71. Blacquie`reT,SmaggheG,vanGestelCAM,MommaertsV: Neonicotinoids in bees: a review on concentrations, side-effects and risk assessment.Ecotoxicology2012http:// dx.doi.org/10.1007/s10646-012-0863-x.

72.

KrupkeCH,HuntGJ,EitzerBD,AndinoG,GivenK:Multiple routesofpesticideexposureforhoneybeeslivingnear agriculturalfields.PLoSONE2012,7:e29268.

Thisstudydescribesexposureofbeestoagrochemicals viamultiple routesthroughoutthegrowingseason.

73.

DiPriscoG,CavaliereV,AnnosciaD,VarricchioP,CaprioE, NazziF,GargiuloG,PennacchioF:Neonicotinoid clothianidin adversely affects insect immunity and promotes replication of a viral pathogen in honey bees.ProcNatlAcadSciUSA2013 http://dx.doi.org/10.1073/pnas.1314923110.

Thisstudywasoneofthefirsttoshowaclearlinkbetweenpesticide exposureandincreasedpathogen load.Furthermore,it wasthefirst studytoproposeamechanismforthiseffectandinvestigateditinboth fruitfliesandhoneybees.

74. HenryM,Be´guinM,RequierF,RollinO,OdouxJ-F,AupinelP, AptelJ,TchamitchianS,DecourtyeA:Acommonpesticide decreasesforagingsuccessandsurvivalinhoneybees. Science2012,336:348-350.

75. GillRJ,Ramos-RodriguezO,RaineNE:Combined pesticide exposure severely affects individual- and colony-level traits in bees.Nature2012http://dx.doi.org/10.1038/nature11585. 76. DoubletV,LabarussiasM,deMirandaJR,MoritzRFA,PaxtonRJ:

Bees under stress: sublethal doses of a neonicotinoid pesticide and pathogens interact to elevate honey bee mortality across the life cycle.EnvironMicrobiol2014http:// dx.doi.org/10.1111/1462-2920.12426.

77. FauconJ-P,AuriresCM,DrajnudelP,MathieuL,RibireM, MartelA-C,ZegganeS,ChauzatM-P,AubertMF:Experimental studyonthetoxicityofimidaclopridgiveninsyrupto honeybee(Apismellifera)colonies.PestManageSci2005, 61:111-125.

78. DivelyGP,EmbreyMS,KamelA,HawthorneDJ,PettisJS: Assessmentofchronicsublethaleffectsofimidaclopridon honeybeecolonyhealth.PLoSONE2015,10:e0118748. Thisstudypresenteddatafromathreeyearstudyonthesublethaleffects ofaneonicotinoidincolony-basedstudiesandfoundadose-dependent effect,thoughfieldrelevantdoseshadanegativeeffect.

79. LawrenceTJ,CulbertEM,FelsotAS,HebertVR,SheppardWS: SurveyandriskassessmentofApismellifera(Hymenoptera: Apidae)exposuretoneonicotinoidpesticidesinurban,rural, andagriculturalsettings.JEconEntomol2016http://dx.doi.org/ 10.1093/jee/tov397.

80. SchmuckR,StadlerT,SchmidtH-W:Fieldrelevanceofa synergisticeffectobservedinthelaboratorybetweenanEBI fungicideandachloronicotinylinsecticideinthehoneybee (ApismelliferaL,Hymenoptera).PestManageSci2003, 59:279-286.

81. DiPriscoG,CavaliereV,AnnosciaD,VarricchioP,CaprioE, NazziF,GargiuloG,PennacchioF:Neonicotinoidclothianidin adverselyaffectsinsectimmunityandpromotesreplicationof aviralpathogeninhoneybees.ProcNatlAcadSciUSA2013, 110:18466-18471.

82. PohanishRP:Sittig’sHandbookofPesticidesandAgricultural Chemicals.WilliamAndrewPub;2014.

83. JohnsonRM,PercelEG:Effectofafungicideandspray adjuvantonqueen-rearingsuccessinhoneybees

(Hymenoptera:Apidae).JEconEntomol2013,106:1952-1957. 84. CoalitionHBH:ToolsforVarroaManagement[Internet].The

KeystonePolicyCenteronbehalfofTheHoneyBeeHealth Coalition;2015.

85. vanEngelsdorpD,EvansJD,SaegermanC,MullinC,HaubrugeE, NguyenBK,FrazierM,FrazierJ,Cox-FosterD,ChenYetal.: Colonycollapsedisorder:adescriptivestudy.PLoSONE2009, 4:e6481.

86. RoseR,PettisJ,vanEngelsdorpD:AUSnationalsurveyof honey-beepestsanddiseases.Internet,www.oie.int. 87. FrancisRM,NielsenSL,KrygerP:Varroa-virusinteractionin

collapsinghoneybeecolonies.PLoSONE2013,8:e57540. 88.

LockeB,ForsgrenE,FriesI,deMirandaJR:Acaricidetreatment affectsviraldynamicsinVarroadestructor-infestedhoneybee coloniesviabothhostphysiologyandmitecontrol.Appl EnvironMicrobiol2012,78:227-235.

Thisstudy was one ofthe first to examine the effects ofacaricide applicationonviraldynamics.

89. vanEngelsdorpD,MeixnerMD:Ahistoricalreviewofmanaged honeybeepopulationsinEuropeandtheUnitedStatesand thefactorsthatmayaffectthem.JInvertebrPathol2010, 103Suppl1:S80-S95.

90. NazziF,LeConteY:Ecology of Varroa destructor, the major ectoparasite of the Western Honey Bee, Apismellifera.Annu RevEntomol2015 http://dx.doi.org/10.1146/annurev-ento-010715-023731.

91. BoncristianiH,UnderwoodR,SchwarzR,EvansJD,PettisJ, vanEngelsdorpD:Directeffectofacaricidesonpathogenloads andgeneexpressionlevelsinhoneybeesApismellifera. JInsectPhysiol2012,58:613-620.

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KusterRD,BoncristianiHF,RueppellO:Immunogeneandviral transcriptdynamicsduringparasiticVarroadestructormite infectionofdevelopinghoneybee(Apismellifera)pupae.JExp Biol2014,217:1710-1718.

Thisisanexcellentinvestigationoftheroleofmitesandvirusinfectionon honeybeeimmunegeneexpression.

93. JohnsonRM,DahlgrenL,SiegfriedBD,EllisMD:Acaricide, fungicideanddruginteractionsinhoneybees(Apismellifera). PLoSONE2013,8:e54092.

94. HopwoodJ,VaughanM,ShepherdM,BiddingerD,MadeE, BlackS,MazzacanoC:AreNeonicotinoidsKillingBees?AReview ofResearchintotheEffectsofNeonicotinoidInsecticidesonBee, withRecommendationsforAction,2012.2016:.xerces.org, accessdateFebruary.

95. CommissionImplementingRegulation(EU)No485/2013[Internet]. 2013,inpress.

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honeybeesrevealshealthierandbroadercommunitieswhen coloniesaregeneticallydiverse.PLoSONE2012,7:e32962 http://dx.doi.org/10.1371/journal.pone.0032962.

98. AndersonKE,CarrollMJ,SheehanT,MottBM,MaesP, Corby-HarrisV:Hive-storedpollenofhoneybees:manylinesof evidenceareconsistentwithpollenpreservation,notnutrient conversion.MolEcol2014,23:5904-5917.

99. KapheimKM,RaoVD,YeomanCJ,WilsonBA,WhiteBA, GoldenfeldN,RobinsonGE:Caste-specificdifferencesin hindgutmicrobialcommunitiesofhoneybees(Apismellifera). PLoSONE2015,10:e0123911.

100.Corby-HarrisV,MaesP,AndersonKE:Thebacterial communitiesassociatedwithhoneybee(Apismellifera) foragers.PLoSONE2014,9:e95056.

101.PfeifferJK,VirginHW:Viralimmunity.Transkingdomcontrolof viralinfectionandimmunityinthemammalianintestine. Science2016,351http://dx.doi.org/10.1126/science.aad5872. 102.MartinezJ,LongdonB,BauerS,ChanY-S,MillerWJ,BourtzisK,

TeixeiraL,JigginsFM:Symbiontscommonlyprovidebroad spectrumresistancetovirusesininsects:acomparative analysisofwolbachiastrains.PLoSPathog2014:10. 103.TeixeiraL,FerreiraA,AshburnerM:Thebacterialsymbiont

WolbachiainducesresistancetoRNAviralinfectionsin Drosophilamelanogaster.PLoSBiol2008,6:e2.

104.JeyaprakashA,HoyMA,AllsoppMH:Bacterialdiversityin workeradultsofApismelliferacapensisandApismellifera

scutellata(Insecta:Hymenoptera)assessedusing16SrRNA sequences.JInvertebrPathol2003,84:96-103.

105.PattabhiramaiahM,BruecknerD,WitzelKP,JunierP,ReddyMS: PrevalenceofWolbachiaintheEuropeanHoneybee,Apis melliferacarnica.WorldApplSciJ2011,15:1503-1506. 106.Corby-HarrisV,SnyderLA,SchwanMR,MaesP,McFrederickQS,

AndersonKE:OriginandeffectofAlpha2.2Acetobacteraceae inhoneybeelarvaeanddescriptionofParasaccharibacter apiumgen.nov.,sp.nov.ApplEnvironMicrobiol2014, 80:7460-7472.

107.Corby-HarrisV,SnyderLA,MeadorCAD,NaldoR,MottBM, AndersonKE:Parasaccharibacterapium,gen.nov.,sp.nov., improveshoneybee(Hymenoptera:Apidae)resistanceto Nosema.JEconEntomol2016http://dx.doi.org/10.1093/jee/ tow012.

108.EngelP,VizcainoMI,CrawfordJM:Gutsymbiontsfromdistinct hostsexhibitgenotoxicactivityviadivergentcolibactin biosynthesispathways.ApplEnvironMicrobiol2015, 81:1502-1512.

109.EngelP,BartlettKD,MoranNA:ThebacteriumFrischella perraracausesscabformationinthegutofitshoneybeehost. MBio2015,6e00193-15.

110.EvisonSEF,RobertsKE,LaurensonL,PietravalleS,HuiJ, BiesmeijerJC,SmithJE,BudgeG,HughesWOH:Pervasiveness ofparasitesinpollinators.PLoSONE2012,7:e30641.

Issue Editorial http://dx.doi.org/10.1016/j.cois.2016.04.009 http://creative-commons.org/licenses/by-nc-nd/4.0/ www.sciencedirect.com 68:810-821. 7:e37235. 14:461-471. 339:1608-1611. 129:617-619. 49:15-22. 108:662-667. 347:1255957. 46:292-305. 2013 30:556-561. 41:256-263. 51:110-114. 2015:. Chen 19:614-620. 41:54. 99:153-158. 7:e43562. 8:72443. 7:3285-3309. 2014, 75:7212-7220. 41:332-352. 2010, 2015. 2015 http://dx.doi.org/10.1016/j.cois.2015.04.016. 108:225-233. 7:3586-3602. 7:3798-3815. 2010,5:e14357. 2015 176:232-240. 104:732-739. 42:650-658. http://dx.doi.org/10.1016/j.jip.2015.12.003 72:606-611. 506:364-366. 9:e113448. 91:2524-2530. 2009, 35:441-448. 86:2281-2289. 336:1304-1306. 10:22-28. 10:170-176. 10:133-141. 2010, 56:1184-1191. 2014, http://dx.doi.org/10.1073/pnas.1303884110 http://dx.doi.org/10.1017/S0031182015001614. 91:61-63. 122:55-58. 129:461-467. 20:249-256. 2015 2008, 10:e0142031. 2010, http://dx.doi.org/10.1146/annurev-ento-011613-162005. 41:312-331. 10:8-13. 2010 2015. 521:74-76. 109:326-329. 2011, 2013, 2012 7:e29268. http://dx.doi.org/10.1073/pnas.1314923110 336:348-350. 2012 2014 61:111-125. 10:e0118748. 2016 59:279-286. 110:18466-18471. 2014. 106:1952-1957. 2015. 2009,4:e6481. 8:e57540. 78:227-235. 2010,103 2015 http://dx.doi.org/10.1146/annurev-ento-010715-023731 58:613-620. 217:1710-1718. 8:e54092. 2016:. 2016:. http://dx.doi.org/10.1371/journal.pone.0032962. 23:5904-5917. 10:e0123911. 9:e95056. 351 2014:10. 2008, 84:96-103. 15:1503-1506. 80:7460-7472. 2016 2015,81:1502-1512. 2015, 7:e30641.

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