Why Do We Feel Sick When Infected—Can Altruism Play a Role?

15 Pages·2015·1.81 MB·English

UNSOLVEDMYSTERY
Why Do We Feel Sick When Infected—Can
Altruism Play a Role?
KerenShakhar1,GuyShakhar2*
1 DepartmentofPsychology,CollegeofManagementAcademicStudies,RishonLeZion,Israel,
2 DepartmentofImmunology,WeizmannInstituteofScience,Rehovot,Israel
*[email protected]
Abstract
Whenwecontractaninfection,wetypicallyfeelsickandbehaveaccordingly.Symptomsof
sicknessbehavior(SB)includeanorexia,hypersomnia,depression,andreducedsocial
interactions.SBaffectsspeciesspanningfromarthropodstovertebrates,istriggerednon-
specificallybyviruses,bacteria,andparasites,andisorchestratedbyacomplexnetworkof
cytokinesandneuroendocrinepathways;clearly,ithasbeennaturallyselected.Nonethe-
less,SBseemsevolutionarilycostly:itpromotesstarvationandpredationandreduces
reproductiveopportunities.HowcouldSBpersist?Formerexplanationsfocusedonindivid-
ualfitness,invokingimprovedresistancetopathogens.Couldpreventionofdiseasetrans-
mission,propagatinginpopulationsthroughkinselection,alsocontributetoSB?
OPENACCESS
SicknessSyndromeandSicknessBehavior
Citation:ShakharK,ShakharG(2015)WhyDoWe
FeelSickWhenInfected—CanAltruismPlayaRole?
Sicknesssyndromeisthegeneralizedresponseofthehosttoinfections.Itsclassicalphysiologi-
PLoSBiol13(10):e1002276.doi:10.1371/journal.
calsignsincludefeverandanemia,butitalsoincludespsychologicalsymptoms—collectively
pbio.1002276
termed“sicknessbehavior”(SB)[1–3].Thesesymptoms,familiartoanyonewhohasbeensick,
Published:October16,2015
includefatigue,depression,irritability,discomfort,pain,nausea,andlossofinterestinfood,
Copyright:©2015Shakhar,Shakhar.Thisisan drink,socialinteractions,andsex.Inanimals,suchchangescanbequantifiedbasedonbehav-
openaccessarticledistributedunderthetermsofthe iorandreflectreprioritizationofmotivationsduringdisease[2].
CreativeCommonsAttributionLicense,whichpermits
Acommonmisconceptionisthatpathogensdirectlyproducethesebehavioralsymptoms,
unrestricteduse,distribution,andreproductioninany
butinfactSBisorchestratedbythehost’simmuneandneuroendocrinesystems;mammals
medium,providedtheoriginalauthorandsourceare
haveevolvedseveralparallelpathwaystoalertthebrainofinflammationandtriggersymptom-
credited.
aticbehaviors(Fig1)[4,5].
Funding:Theauthorsreceivednospecificfunding
Althoughthespecificitiesmayvary,SBiswidespreadwithrespecttobothpathogensand
forthiswork.
hosts:diversepathogens,includingviruses,bacteria,andprotozoa[1],cantriggerit,andequiv-
CompetingInterests:Theauthorshavedeclared
alentbehavioralresponsescharacterizeseveralvertebrateclasses[1,2,7]aswellasarthropods
thatnocompetinginterestsexist.
[8,9].However,whencloselyexamined,somegeneraexhibitsignificantvariationintheextent
Abbreviations:CCD,collapsedcolonydisease; ofSB[10],whichtodateremainsunexplained.
COX,cyclooxygenase;DC,dendriticcell;ESS,
evolutionarilystablestrategy;IL,interleukin;LPS,
lipopolysaccharide;NLR,NOD-likereceptor;NTS, TheMystery—WhyDoWeFeelSick?
nucleusofthesolitarytract;SARS,severeacute
SinceSBisaconservedphenomenonthatismediatedbycompleximmunologicalandneuro-
respiratorysyndrome;SB,sicknessbehavior;TLR,
toll-likereceptor;TNF-α,tumornecrosisfactoralpha. endocrinepathways,itclearlymusthaveevolutionarybenefits.Still,inthelast25years,much
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Fig1.Informationregardinginflammationiscommunicatedtothebrainthroughparallelneuraland
circulatoryroutes[4,5].Leukocytes,suchasdendriticcells(DCs)andmacrophages,sensemicrobes
throughpathogen-recognitionreceptorssuchastoll-likereceptors(TLRs)andNOD-likereceptors(NLRs)
andthenreleaseinflammatorycytokinessuchasinterleukin–1beta(IL–1β),IL–6,andtumornecrosisfactor
alpha(TNF-α).Intheneuralroute,cytokinestriggeractivityinvagalafferentsthatinnervatenucleiinthebrain
stemsuchatthenucleusofthesolitarytract(NTS).Theseinturnrelaythesignaltovariousnucleiinthe
hypothalamus,thalamus,andamygdala[4].Inthecirculatoryroute,microbialligandsandcytokinestravel
throughthebloodtoreachthemeninges,choroidplexus,andcircumventricularorgans(pink)wheretheycan
enterthebrain.Morerecentdataindicatethatsuchligandscanalsoactivatetheepitheliuminareaswithan
intactblood–brainbarrier,causingittosynthetizevariousprostaglandinsandreleasethemintonuclei
involvedinspecificbehaviors[6].
doi:10.1371/journal.pbio.1002276.g001
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efforthasbeendirectedatunderstandingtheproximatereasonsforSB[3],butitsultimatecau-
sation—thereasonsSBhasevolvedinthefirstplace—attractedrelativelylittleattention.
Unlikephysiologicalsymptomsofsickness,suchasfeverandhypoferremia,whichlikely
boostresistancetopathogens(Box1),behavioralsymptomsremainpoorlyexplained.Clearly,
allofthesesymptomsimposesignificantcoststohostfitness(Fig2)[11,12].Anorexiaand
adipsiaincreasetheriskofstarvation,lossofessentialnutrients,anddehydration,particularly
inthecontextoffever.Lethargycanleadtopredationbyslowingdownpreyandsinglingitout
forpredators[13,14].Socialdisinterestdecreasesparentalcare[15,16],limitsmatingopportu-
nities[17],and,togetherwithfatigue,canleadtolossofterritoryandsocialstatus[7,18].For
SBtoevolve,thesecostsmustbeoffsetbybenefits—whatcanthesebenefitsbe?
Box1.FeverandHypoferremia:PhysiologicalManifestationsof
SicknessSyndrome
Physiologicalresponsestosicknessareinitiatedbytheimmunesystemandpropagated
mainlybythebrainandliver.Manyofthesearebelievedtobenefithostresistancetoinfec-
tions,andtwo,feverandanemia,havebeenlinkedtoSB[1].
Feveriswidelybelievedtoimprovesurvivalfollowinginfection[19,20]bydirectly
inhibitingthegrowthofvariouspathogensandbyenhancingimmunefunction(e.g.,bac-
terialclearance,Tcellproliferation,andneutrophilactivation)[21].Thebenefitsofhyper-
thermiahasbeenmostconvincinglydemonstratedinectodermssuchasreptilesandfish,
inwhichdeliberateexposuretohigherenvironmentaltemperaturesimprovedsurvival
[19].Correspondingly,inrabbits,mice,andchicks,antipyreticdrugsrepeatedlyincreased
mortalityratesfrombacterial[22]andviral[23]infections.Theevidenceinhumansisless
conclusive,aslarge-scaleblindedtrialshavenotbeenperformed[24,25].Nonetheless,sev-
eralsmallrandomizedtrialshavereportedthatantipyrogenicagentsdelayedrecovery
frominfectionssuchasmalaria[26–28]andchickenpox[29].Consequently,ithasbeen
estimatedthatroutinelytreatinginfluenzapatientswithantipyreticscausesatleast700
extradeathsannuallyintheUnitedStatesalone[20].
Anotherphysiologicalcomponentofsicknesssyndromeisanemia,whichisabyproduct
of“hypoferremiaofinfection.”Hypoferremiaisawell-regulatedprocessintendedto
deprivepathogensoftheironessentialfortheirgrowth[30,31].Itaffectsseveralclassesof
pathogens,includingmanybacteria,someviruses,andseveralprotozoa.Freelyavailable
ironcandiminishnormalresistancetobacteriainseveraldiseases,andironoverload
increasedinfectionratesofpathogenssuchastuberculosis,malaria,andbrucellosis[31,32]
Infectionelicitshypoferremiaaspartofthehepaticacutephaseresponse[31].Inflamma-
torycytokinessuchasIL–6,IL–22,andtype-Iinterferonstriggertheproductionofthepep-
tidehormonehepcidinintheliver.Hepcidinthenbindsandinternalizestheironexporter
proteinferroportin.Asaresult,macrophagestraptheironrecycledfromerythrocytes,and
enterocytesstoptransferringdietaryirontothecirculation,rapidlyreducingplasmairon.
CanSBImproveHostResistance?
TheconceptthatSBisacoordinatedandadaptiveresponsetoinfectionshasbeenestablished
sincethemid-1980s.Severalcomprehensivereviewshavecoveredthehistoricaldevelopment
ofthisconceptandconsideredvarioushypothesesregardingtheadaptiveroleofSB[2–
4,14,33].
EarlyfindingssuggestingthatSBdirectlybenefitsthehostexaminedanorexia.Inawell-
controlledstudyfrom1979,MurrayandMurrayinfectedmicewithListeriamonocytogensand
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Fig2.ThecostsofSBtodirectfitness.Behavioral(pink)andphysiological(green)symptomsofSBcan,eitherdirectlyorindirectly,leadtomaladaptive
consequences(orange)thatreduceindividualfitness.
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force-fedthemtocompensatefortheresultantanorexia[34].Thetreatedmicesuccumbedto
theinfectionathighrates.Unliketheadaptiveeffectsoffever,thisremainedalargelyisolated
study,andcontestingtheoriesstilldebatewhetheranorexiaboostsresistancetopathogensand
howitmightdoso[35].Suggestionsincludeddeliberaterestrictionofnutritionalelements,
avoidingpotentiallycontaminatedfood,andadecreaseinriskyforagingwhileweak[35].
Newlyestablishedrouteslinkingnutrition,intestinalmicrobiota,andimmunity[36]cannow
alsobeconsidered.
In1988,aseminalpaperbyBenjaminL.HartwasthefirsttosuggestthatSBinitsentirety
isacoordinatedresponsebenefittingthehost[1].Realizingthatfeverandhypoferremia
directlypromotehostdefense(Box1),HartsuggestedthatSBisprimarilyintendedtoserve
thesephysiologicaladaptations.Specifically,heproposedthatSBevolvedtoconserveenergy
neededtosustainmetabolicallydemandingfever.Thus,immobility,lethargy,andreduced
motivationtoobtainfoodanddrinkcouldhavedevelopedtominimizemuscleworkandexpo-
suretothecold.Anorexia,ontheotherhand,wouldpromotehypoferremiabyreducingiron
intake.Otherbehaviorswereviewedassubordinatetotheprimaryonesthatconserveenergy
andreduceiron.Reducedgrooming,forexample,couldpreservefluidsinthecontextofadip-
sia,whereasdecreasedforagingwouldprotectaweakanimalfrompredators.
Hart’shypothesisremainedthedominanttheoryinthefield[2,37–40],asitparsimoniously
explainsalargerangeofsymptoms.Sinceitwasproposed,though,accumulatedevidencehas
exposedsomegapsinthehypothesis;itisnowtimetoreassessit.
ConservingenergytomaintainfeveriscentraltoHart’shypothesis.SBisdefinitelyassoci-
atedwithreducedmotivationforaction—andthereforewithlessenergyexpenditure.However,
inmanycases,feverandSBaredecoupled,theonearisingwithouttheother[10].Inhumans,
forinstance,malaiseandfatigueoftencharacterizemildinfectionsthatdonotelicitfever.
Moreimportantly,severalaspectsofSBcanactuallytiptheenergybalanceinthewrongdirec-
tion.Confinementtonestsanddensdoesnotalwaysconserveheat.Inwarmerclimates,dens
arecoolerthantheoutsideenvironmentandmobilityincreasesbodytemperature,yetdesert
animalsstillremaininside[10].Anothercounterproductivesymptomisreducedgrooming.
Whenmammalsandbirdsstopgrooming,theirfurandplumagegraduallylosetheirinsulating
efficiency,requiringmoreenergytomaintainfever[41,42].
Themostcounterintuitivesymptomisanorexia,which,asHartacknowledged,deprives
sickanimalsofcaloriesneededtofuelfever(especiallyinmigratoryanimalsthatcannotreduce
energyexpenditurebyretiringtoprotectedenvironments).Recognizingthiscaveat,Hartsug-
gestedinsteadthatanorexiaevolvedtoreduceironconsumption,consequentlyassisting
anotherimportantantimicrobialresponse—hypoferremia.Itseemsunlikely,though,thatevo-
lutionwouldfavoranindiscriminatereductioninfoodintakejusttodecreaseironconsump-
tion.Herbivores,forinstance,canvarytheirdiettosuitnutritionalneeds[43],sotheycould
insteadavoidonlyiron-richfoodsoringestclayeysoiltointerferewithironabsorption[44].
Moreimportantly,physiologistshavesincegainedmuchmechanisticinsightintohypofer-
remia,renderingthisnotionlesslikely.Dietaryironabsorptionisdwarfedbythetotaliron
reservesinthehumanbodyandtheamountrecycledthrougherythropoiesis[45].Anorexia,
therefore,canonlymediateslow-actingchangesinplasmairon[46].Incontrast,inflammatory
agentssuchaslipopolysaccharide(LPS)canhalveplasmaironwithinafewhours[47].The
directmechanismthroughwhichinfectionelicitshypoferremia(Box1)wasonlydiscovered15
yearsago[31]andinvolvestherapidproductionofhepcidinintheliver.Thisefficientmecha-
nismobviatesanorexiawheninfectionrequiresthehosttorapidlyreduceplasmairon.
SensingthatHart’sexplanationcannotaccountforallthesymptomsofSB,severalcomple-
mentarytheorieshavesincebeenproposed.WatkinsandMaier[48]stressedtheimportance
ofallodyniaandhyperalgesia(reducedthresholdandincreasedintensityofpain)inSB.They
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proposedthatthesesymptoms,togetherwiththereducedactivitySBintroduces,areintended
toprotectsensitiveorgansandtissuesfromfurtherdamage.Medzitovetal.[49]maintained
thatSBchieflypromotestolerancetowardsparasites,ratherthantheirclearance,althoughthe
detailsofthisinteractionremainedunclear.Allthesetheoriesfocusondirectbenefitsthat
infectedindividualsmayderivefromSB;theydisregardtheindirecteffectsSBmayhaveatthe
grouplevel.
Overall,theevidencethatallthesymptomsofSBdirectlyimprovehostresistancetoinfec-
tionremainsincomplete,andafterseveraldecadesofresearchinthisfield,writersstilldebate
whetherandhowsymptomsofSBbenefithosts[3,14,33,35,50].What,then,couldacomple-
mentaryevolutionaryexplanationbe?
CouldKinSelectionDrivetheEvolutionofSB?
IfgainstodirectfitnesscannotfullyexplainSB,perhapsinclusivefitnesscouldcomeintoplay.
Weproposethatreducedtransmissionofinfectiousdiseaseamongrelatedindividualscontrib-
utedtotheevolutionofSB.AlthoughtheideathatSBreducestransmissionhasbeenalludedto
before[3,20,51,52],itwasneverrecognizedasamajororganizingprincipleforSBinverte-
brates.Wenamethistheory“theEyamhypothesis”aftertheEnglishminingcommunitythat
isolateditselftocontainanoutbreakofbubonicplaguein1666.Three-quartersofthevillagers
reportedlydied,butthesurroundingcommunitiesweresaved[53].
TheEyamhypothesisreliesonthreepremises:
Premise1:SBReducesDirectandIndirectContactsbetween
InfectedIndividualsandTheirConspecifics
Strikingly,mostofthesymptomsthatconstituteSBshareacommondenominator:theyrestrict
contactsbetweensickindividualsandtheirsocialgroups(Fig3).Symptomsofsicknessachieve
thisfeatusingthreecontainmentstrategies:
ContainmentStrategy#1:RestrictingPhysicalContacts
Itisself-evidentthatsalientsymptomsofSB,suchassocialdisinterest,depression,hyperalge-
sia,fatigue,andhypersomnia,reducethemobilityandsocialactivityofinfectedindividuals,
limitingtheircontactwithconspecifics.Likewise,sexualdisinterestsuppressescourtshipand
matingbehaviors,whereasreducedparentalcareentailsbydefinitionlessinteractionwithoff-
spring.Thecontributionofanorexiaandadipsiamaybelessapparent;bysuppressingthe
motivationtoeatanddrink,theyreducetheurgetotravelinsearchoffoodandwater,share
mealswithgroupmembers,andgatheratwatersources.
Self-imposedisolationmayaccountforthefolkobservationthatterminallyilldogsleave
theirownerstodiealone.Similarbehaviorhasbeenrecordedinthewildamongbadgers,
which,wheninfectedwithbovinetuberculosis,separatedfromtheirclanandsettledinindivid-
ualsetts,wheretheydied[54].
Tellingly,theoppositeeffectisobservedwhenpathogensmanipulatehostbehaviortotheir
benefit.Insuchdiseases,infectedhostsbecomehyperactiveandinteractmorewithpotential
hosts:forexample,rabiddogsbecomefearlessandbite,androdentsinfectedwithToxoplasma
gondiilosetheirfearofcats(thedefinitivehosts)[55].
ContainmentStrategy#2:LimitingEnvironmentalContamination
Ontopofrestrictingdirectcontacts,SBcanalsolimitindirectcontactsbetweenconspecificsby
reducingmicrobialcontaminationofsharedresources:ground,foodandwater(Fig3).
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Fig3.ThebenefitsofSBtoindirectfitness.SymptomsofSB(pink)cansuppress(redconnectors)or
promote(greenarrows)severalmediatingbehaviors(yellow),consequentlyreducingpathogentransmission
throughseveralroutes(blue).
doi:10.1371/journal.pbio.1002276.g003
Symptomssuchashypersomnia,fatigue,anddepressionrestricttheanimal’sradiusofactiv-
ity,limitingenvironmentalcontaminationtoitsimmediatesurroundings.Socialandsexual
disinterest,aswellasanorexiaandadipsia,furtherreducethedriveofanimalstotravelfarther
afield.
Anorexiaandadipsiaseemparamountinthatrespectastheypreventsickanimalsfrom
contaminatingsharedfoodandwaterresources.Contaminationofpastures(forherbivores)or
carcasses(forcarnivores)andcontaminationofwaterholesareundoubtedlymajorroutesfor
oralandfecal-to-oraltransmissioninthewild.Finally,anorexiaandadipsiaalsoreducedefeca-
tion,diarrhea,andvomiting,whicharethemajormeansofspreadingforentericpathogens.
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ContainmentStrategy#3:AdvertisingInfectiontoConspecifics
Whereasstrategies#1and#2involveself-imposedrestrictions,SBcanalsoactbyprovoking
responsesfromconspecifics.Inmanyspecies,groupmemberscandetectinfectedindividuals
throughvisual,olfactory,andchemicalcues[56–59],distancethemselves,andstopinteracting
withthem[60].Suchsignalinghasbeendemonstratedmostconvincinglyineusocialinsectsin
whichchemicalcommunicationisusedtocoordinatesocialimmunity(Box2).
Box2.TheCaseforSocialImmunityinEusocialInsects
Eusocialinsects—socialbeesandwasps,ants,andtermites—formcoloniesdubbed“super-
organisms.”Thesecontainfewbreedingindividualsandmanycloselyrelatedsterilework-
ers.Workersaredispensable,carecollectivelyforbrood,andaregeneticallyinvestingin
theirsiblingsandparents.Thissituationencouragescooperationandaltruism.Coloniesof
eusocialinsectsareidealsettingsforthespreadofpathogens,astheirinhabitantsliveat
highdensity,constantlytouchoneanother,andexchangefoodorally.Lowgeneticdiver-
sitymayposeanadditionalrisk,asmoreindividualsaresusceptibletothesamepathogens.
Theoretically,thesefactorsmakeeusocialinsectsoptimalcandidatestodevelopSB.
Empirically,ithaslongbeenrecognizedthateusocialinsectsexhibitsocialimmunity,
collectivebehaviorsthatpromoteparasiteresistance[61]andlimitcontagiousinteractions
amonggroupmembers[62].ManyofthesebehaviorsresembleSBinvertebrates,whereas
someareidiosyncraticadaptationstothesituationininsectcolonies.
Specifically,amongseveralspeciesofants,individualsthathadbeenexperimentally
treatedwithlivepathogensorpathogen-associatedmolecules(suchasLPS)arelesssocia-
ble[8],avoidcontactingbrood[8,63],stoptransferringfoodtonestmates(trophallaxis)
[9],becomelessmotile[9],decreaseallogroomingofnestmates[64],andspendmostof
theirtimeoutsidethenest,wheretheyeventuallydie[8,65].Similarly,amonghoneybees,
individualswhosehealthiscompromisedeatless,transferlessnectartothehive[66],
spendlesstimeinthehive[67],andleaveittodieinisolation[66].Thiscompulsionto
leavethehivemayexplainsuddenmassdesertionsobservedintherecentepidemicofcol-
lapsedcolonydisease(CCD),regardlessoftheelusivepathogenthatinducesit[68].The
behaviorofparasitizedtermiteshasbeenlessstudied,butinfectedindividualsseemto
migratetobottomstrataofmoundsanddiethere[69].
Communicatinghealthstatusisanimportantaspectofsocialimmunity.Thebulkof
ourknowledgeconcerns“hygienicbehavior”inhoneybees.Inthisprocess,infectedlarvae
andpupaearedetectedandremovedfromthehivebyworkers,limitingthespreadof
infections[70,71].Evidently,thebroodcommunicatesitshealthstatuschemicallyatthe
earliestsignofinfection.Recently,itwasshownthatadultbeescanalsobeexpelledfrom
thehivebasedonsimilarsignals[71].Thebehavioralcomponentofsuchsignalingis
clearerindampwoodtermitesinwhichadultsthathavecontactedfungalsporessignal
throughvibrationtorepelcolonymembers[60].
Studiesinrodentsimplicatedthevomeronasalorganinsensinginfection[72]anddiscour-
agingsocialandsexualinteractions[59];importantly,immuneactivationwithLPSwasenough
tomarkanimalsassick.Eveninhumans,mammalswithanill-reputedsenseofsmell,the
clothesofLPS-treatedsubjectscanbesniffedout[73].
Itiseasytoacceptthatthedetectionofinfectedconspecificshasevolvedasaprotective
avoidancemechanism,butthetransmissionofsuchsignalscouldalsohavebeenselectedfor.
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SeveralsymptomsofSBmayactasinfectioncues:reducedself-groomingvisiblydistinguishes
infectedindividualsasscruffy[1]andprobablyaccentuatestheolfactorysignalstheyemit.
Similarchangesmayaffectvocalcommunication.Insparrows,forinstance,thefrequencyand
patternofbirdsongchangeduringaninflammatoryresponse[74].Lastly,thestereotypicpos-
tureandmotionthatinfectedanimalsadoptbecauseoffatigueandhyperalgesiacanactas
additionalcues.Thus,LPS-treatedsubjectscanbedetectedbyobserversbasedontheirgait
[75].Thesignalingaspectsofsuchbehavioralchangesareexposedbytheresponseofsickani-
malstopredators.Underthegazeofcarnivores,sickmembersofaherdwouldattempttodis-
guisetheirvulnerabilityandsuppressSB[14].Thisobservationsuggeststhatanimalscanalert
theirkinofinfectionbutsuppresssuchsignalingtopredators.
Premise2:ReducedContactsLimittheSpreadofInfections
Medicinehaslongacknowledgedtheimportanceofisolationforcontaininginfectiousdisease
inhumans.Behavioralinterventionssuchasquarantine,schoolclosures,andbansontravel
andpublicgatheringhavecurtailedthespreadofcontagiousdiseasessuchasEbola[76],vec-
tor-mediateddiseasessuchasbubonicplague[77],andairborneonessuchassevereacute
respiratorysyndrome(SARS)[78].Thesesuccessesdemonstratethat,regardlessoftheroute,
socialisolationcanreducetransmission.
AquestionmorerelevanttotheevolutionofSBiswhetherself-imposedsocialisolationis
effectiveinthewild.Severalsuchexamplesexist:inthelastdecade,batpopulationsofmany
speciesinNorthAmericacollapsedbecauseofthe“whitenose”fungaldisease.Although
almostallofthecoloniesobservedweredecimated,somebatpopulationssurvivedbyadopting
asolitaryroostingpattern[79].Conversely,astudyinwilddeermicehasshownthathighly
activeindividuals,whichencounteredmoremice,exhibitedhigherviralinfectionrates[80].
Isolationofinfectedpeoplebasedonclinicalsymptomscanbeeffectiveonlywhenthey
overlapwiththeinfectiousperiod[81].Empiricaldatasuggestthat,inthefewinfectiousdis-
easesstudied(barringHIV),thisisindeedthecase.Thus,inSARS,smallpox,andfoot-and-
mouthdisease,thisoverlapexceeds80%[81,82],andestimatesforinfluenzarangebetween
50%and90%[81,83].Sincebehavioralsymptomstypicallyprecedespecificclinicalsigns,these
figureslikelyunderestimatetheoverlapbetweenSBandinfectivityandthepotentialreduction
intransmission.
Premise3:BehaviorsThatReducePathogenTransmissionCan
PersistthroughKinSelection
IfindeedSBfavorsthefitnessofothergroupmembersattheexpenseoftheindividuals,thenit
canbeconsideredaninstanceofbiologicalaltruism.Ithaslongbeendebatedhowaltruismcan
becomeanevolutionarilystablestrategy(ESS).Alikelymechanismiskinselection,thepositive
selectionoftraitsthatincreasethefitnessoftheindividual’srelatives.Thisinitiallycontrover-
sialtheory,putforwardbyW.D.Hamilton[84],hasbeenmathematicallyvalidatedandwidely
acceptedsince[85].
Kinselectioniseasytoacceptwhenaltruismisactivelydirectedatrelatives(e.g.,birdsfeign-
inginjurytoleadpredatorsawayfromtheirchicks),buthowcanitpromoteSB,aresponse
thatindiscriminatelyfavorsrelatedandunrelatedgroupmembers?Thiscanonlyhappenwhen
theaveragerelatednesswithinthesocialgroupishigherthanwithintheentirepopulation.
Indeed,inmany(althoughcertainlynotall)species,geneticallyrelatedindividualsaredispro-
portionallyrepresentedintheimmediatesocialgroupsinwhichmostphysicalinteractions
occur[86–89].Suchbiasdevelopsbecauseofhighpopulationviscosity,i.e.,slowandspatially
restricteddispersalofprogeny.
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Animalspeciesvaryinthedegreeofintergrouprelatednessbasedontheirlifehistory.At
oneendofthespectrumarer-strategistswhoseoffspringareneonatallyindependentanddis-
persewidely.Undersuchconditions,socialconsiderationsareunlikelytodriveSB.Atthe
oppositeendofthespectrumlieeusocialanimals.Amongthese,eusocialhymnopterahave
beenstudiedmost(Box2).Theseinsectsindeeddisplayavarietyofcollectivediseasedefense
behaviors,inpartresemblingSB,whicharecollectivelytermed“socialimmunity”[61].
Humans,classicalK-strategistswhocohabitmostoftheirliveswithfirst-degreerelatives,seem
tolieclosertothispole.
Intriguingly,someexperimentalevidencesuggeststhatSBisactuallynotasuniversalascom-
monlyassumed.Somebirdscanbecomeinfected,mountanimmuneresponseanddevelopfever
withoutshowingconspicuoussignsofillness[90],leadingtoanapparentlysuddendeathfrom
infection[14].Infish,administrationofLPStriggersnoobservablebehavioralchanges[91].
StudiesinwildmousepopulationsshowedthattheintensityofSBvariesconsiderablyamong
relatedspecies[10].Howthisdiversityrelatestosocialstructureisyettobeexamined.
WhereDoWeGofromHere?
TheEyamhypothesishasneverbeendirectlytested,sotheempiricalevidencesupportingitis
stilllimited;nonetheless,itproducestestablepredictions.Asstatedabove,anESSforSBwould
counterbalanceitscosttotheinfectedindividualswiththebenefitofreducingtransmissionto
theirkin.Thisbenefitshouldbeproportionaltopathogenvirulence,thechancesoftransmis-
sionbetweenindividuals(infectivity),andtheaveragerelatednessofsusceptiblehosts.Conse-
quently,severalpredictionscanbeexaminedeithercorrelatively(1-3),experimentally(4,5),or
mathematically(6,7).
1. Virulence:DifferentpathogensinvokeSBofvaryingintensities.Ourtheorypredictsthat,
throughanevolutionaryprocess,morevirulentpathogenswouldcometoprovokestronger
behavioralresponses.Whenapathogenisdeadly,theindividualloseslittle(asitwoulddie
anyway)andgainsmuch(asitsavesitsrelativesfromdeath)fromadebilitatingbehavioral
response.Whenapathogenisavirulent,theoptimalbehavioralresponsewouldbeasub-
clinicalone,invokingnoSBevenifanimmuneresponseisactivated.
2. Diseasetransmission:IncreasedoddsfortransmissionwouldalsofavoravigorousSB.
Thus,moreintenseSBisexpectedamongspeciesthatliveindensecoloniesandengagein
closephysicalcontact(especiallyingregariousseasons).Likewise,highlycontagiouspatho-
gensareexpectedtotriggeramorepronouncedSB.
3. Geneticrelatedness:HigherrelatednesswithinsocialgroupsshouldalsopromoteSB(asit
wouldotheraltruisticbehaviors).Thus,SBwouldintensifywithpopulationviscosityand
thelengthofcareforoffspring.Thiscouldbetestedbycomparingphylogeneticallyclose
species(e.g.,socialversussolitarywasps).Comparisonscanalsobemadeamongindividuals
withincommunities:forexample,mothersversusfathersinpolygamousspeciesandrepro-
ductiveversusnonreproductivemembersofeusocialcommunities.
4. Anti-inflammatorydrugs:PharmacologicallysuppressingSBinexperimentallyinfected
individualsshouldacceleratethespreadofinfectionsevenwhenthecourseofdiseaseis
unaltered.Suchexperiments,though,wouldrequirehabitatsthatallowefficientself-
isolation.
5. Tracers:Toruleoutimmunologicaleffectsonpathogenclearance,thedispersalofinnocu-
oustagssuchaspigmentsorradioisotopescanbetraced.
PLOSBiology|DOI:10.1371/journal.pbio.1002276 October16,2015 10/15