h tt p : / / w w w . b j m i c r o b i o l . c o m . b r /
Medical
Microbiology
Brazilian
borreliosis
with
special
emphasis
on
humans
and
horses
Roberta
Carvalho
Basile
a,∗,
Natalino
Hajime
Yoshinari
b,
Elenice
Mantovani
b,
Virgínia
Nazário
Bonoldi
b,
Delphim
da
Grac¸a
Macoris
a,
Antonio
de
Queiroz-Neto
aaUniversidadeEstadualPaulista,FaculdadedeCiênciasAgráriaseVeterinárias,Jaboticabal,SãoPaulo,SP,Brazil bUniversidadedeSãoPaulo,Departamentodereumatologia,SãoPaulo,SP,Brazil
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Articlehistory:
Received5November2015 Accepted20May2016
Availableonline4October2016 AssociateEditor:MilianeMoreira SoaresdeSouza Keywords: Borreliaburgdorferi Zoonosis Ticks Equine Baggio-YoshinariSyndrome
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BorreliosiscausedbyBorreliaburgdorferisensulatoisacosmopolitanzoonosisstudied world-wide;itiscalledLymediseaseinmanycountriesoftheNorthernHemisphereandLyme-like orBaggio-YoshinariSyndromeinBrazil.However,despitetheincreasingnumberofsuspect cases,thisdiseaseisstillneglectedinBrazilbythemedicalandveterinarycommunities. BrazilianLyme-likeborreliosislikelyinvolvescapybarasasreservoirsandAmblyommaand
Rhipicephalusticksasvectors.Thus,domesticanimalscanserveaskeycarriersinpathogen dissemination.ThiszoonosishasbeenlittlestudiedinhorsesinBrazil.Thefirstsurveywas performedinthestateofRiodeJaneiro,andthisBrazilianBorreliosisexhibitsmany differ-encesfromthediseasewidelydescribedintheNorthernHemisphere.Theetiologicalagent showsdifferentmorphologicalandgeneticcharacteristics,thediseasehasahigher recur-rencerateaftertreatmentwithantibiotics,andthepathogenstimulatesintensesymptoms suchasabroaderimmuneresponseinhumans.Additionally,theBrazilianzoonosisisnot transmittedbytheIxodesricinuscomplex.Withrespecttoclinicalmanifestations, Baggio-YoshinariSyndromehasbeenreportedtocauseneurological,cardiac,ophthalmic,muscle, andjointalterationsinhumans.Thesesymptomscanpossiblyoccurinhorses.Here,we presentacurrentpanelofstudiesinvolvingthediseaseinhumansandequines,particularly inBrazil.
©2016SociedadeBrasileiradeMicrobiologia.PublishedbyElsevierEditoraLtda.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/
licenses/by-nc-nd/4.0/).
Lymedisease(LD)orLymeborreliosis(LB)isthemost com-montick-bornediseaseintemperateregionsoftheNorthern HemisphereandiscausedbythespirocheteBorreliaburgdorferi
sensulato.1LDisamultistagediseasethatcanaffectmultiple organsbutinhumansmanifestspredominantlyintheskin, joints,andnervoussystem.2
∗ Correspondingauthor.
E-mail:basile.roberta@gmail.com(R.C.Basile).
History
In1976,childreninageographicalregionoftheUnitedStates, specificallynearthetownofLyme,Connecticut,wereaffected byamysterioussyndrome3 thatwasinitially diagnosedas
http://dx.doi.org/10.1016/j.bjm.2016.09.005
1517-8382/©2016SociedadeBrasileiradeMicrobiologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
juvenilerheumatoidarthritis.1In1981,theentomologistand
physicianWillyBurgdorfer,alongwithAlanBarbourandJorge Benach,foundaspirocheteinthemidgutofticksofthegenus
IxodesinanareaofNewYork,aknownendemicfocusofLD. Theresearcherscultivated samples from ticks ina culture mediumdevelopedforgrowingtherelapsingfeverspirochete (B.hermisii)andfoundanewspeciesofBorrelia,subsequently namedB.burgdorferi.4Later,thesamebacteriumwasisolated
andcultivatedfromthebloodofpatientswithLD.
Thediseases termed Lyme borrelioses are known to be causedbyalargenumberofspeciesrelatedtoB.burgdorferi,
whicharecalledB.burgdorferisensulato.5Ofthe34existing Borreliaspp.,20arereferredtoasBorreliaburgdorferisensulato andcauseLD,whichistransmittedbyticksofthegenusIxodes.
Ofthese20species,onlyninehavebeenisolatedfromhumans intheNorthernHemisphere(B.afzelii,B.bavariensis,B.bissetti, B.burgdorferistrictosensu,B.garinii,B.kurtenbachii,B.lusitaniae, B.spielmanii,andB.valaisiana).6
ThefirstisolationofB.burgdorferisensulatointheSouthern HemispherewasperformedbyBarbierietal.inUruguayfromI. pararicinusticks.Thereafter,thebacteriumwasalsoidentified inArgentina7 andChile,8,9 whereitwas namedB.chilensis.
Allthreeisolationsrevealedthebacteriuminticks oftheI. ricinuscomplexusingamplificationofthe16Sribosomalgene, 5S-23Sintergenicspacer, andflagellingene (fla)forspecies identification.
B.burgdorferisensulatoisahighlyinvasivegram-negative spirochete. Itspathogenicitydepends onits mobility, cyto-toxicity, antigenic variability, lymphocyte stimulation, and resistancetocomplementactivationintheabsenceofspecific antibodies.10
Transmission
Thepathogen is mainly transmittedby ticks of the I. rici-nus complex.11 However,there are reports ofB. burgdorferi
s.l. transmission byAmblyomma americanum inFlorida and GeorgiaintheUnitedStates.12Ithasalsobeenidentifiedin DermacentornitensinthestateofParaná,Brazil.13
Thebacteriacaninfectthetickwhenitfeedsonaninfected reservoirhost.11Aftermoltingtothenymphstage,theticks
areabletotransmitthepathogentotheanimalfromwhichit obtainsitsnextbloodmeal.Astranstadialtransmissionisnot alwayssuccessful,transmissionofthebacteriaisensuredby anenzooticcycleinwhichthetickfeedsonvariousvertebrate hosts.14
Thespirochetesaredepositedintothebitewoundalong withtheticksaliva.For infectiontosucceed,the tickmust feedforatleast24hadheredtothehost,aperiodafterwhich thereisreducedexpressionofOuterSurfaceProteinsAand B(OspAandOspB)andincreasedexpressionofOuterSurface ProteinC(OspC).OspAsandOspBsarelipoproteinsessential forthesurvivalofBorreliaspp.inthetickmidgut.OspCis cru-cialforestablishinginfectionintheinvertebratehostbecause theproteinallowsthebacteriatomigratefromthetickmidgut tothe salivaryglands,where theywillbecarried withthe salivatothevertebratehost.15 OspCalsohasanimportant
roleinthe vertebratehostbecauseit induces immunosup-pression,therebyfavoringinfection.14Tillyandco-workers16
foundthatbacterialackingOspCdonotestablishinfectionin micebyeitherbacterialinoculationviainjectionorbytickbite.
Immune
response
Inthevertebratehost,Borreliaspp.arerecognizedbyseveral mechanismsoftheimmuneresponse,includingthe comple-mentsystemanddiverseinnateimmunecells.17Despitebeing
classified asgram negative,B. burgdorferidoes notproduce lipopolysaccharide(LPS)butdoesexpressOspCinvertebrates. Recognition ofBorrelia spp.bydendritic cellsleads to mat-uration of these cells and triggers transcription of a large setofgenes,suchasthoseexpressingchemokines, apopto-sisinhibitors,matrixmetalloproteasesandalargesubsetof cytokines,includingproinflammatorymediators,neutrophils attractants,immunomodulatorycytokines.18
Following antigen presentation by dendritic cells, TH1
and TH2 lymphocyte helper T cells initiate the adaptive
response,promotingthereleaseofinterferonIFN-␥and inter-leukin IL-4, which are directly related to the severity of acutesymptoms.17Subsequently,thecytokinesreleasedbyT
H
cellsinduceB-lymphocyteproliferationofandconsequently, immunoglobulinproduction.18
Althoughtheimmunesystemattemptstoprevent Borre-liainfection,thespirochetehasitsownmechanismstoavoid hostdefenses.Componentsofthetick’ssaliva(suchasSalp15)
areknowntobeabletosuppressthedendriticcellresponse, increasingthepathogenic virulenceofBorrelia.17The
spiro-chetes canalsoinactivatethe hostcomplement systemby bindingtohostcomplementregulatoryproteins,thereby inac-tivatingtheC3bmechanism.Anothermechanismemployed byBorreliatoescapetheimmuneresponseisantigenic vari-ation.The variablemajor protein-likesequence genelocus (vlsE)onplasmid28-1undergoesextensivevariation,which isstimulatedbytickfeeding.18
The
disease
in
humans
(LD
of
the
Northern
Hemisphere
versus
Brazilian
Baggio-Yoshinari
Syndrome)
Acute LD is typically manifested by an expanding ery-thematous skin lesion. Late manifestations may include arthritis, acrodermatitis chronica atrophicans, lymphocy-toma, myocarditis, conjunctivitis, uveitis, and neurological signs.19
TheexistenceofborreliosisinhumansinBrazilwasfirst suggestedbyDr.Yoshinariandco-workers20;however,thefirst
caseinthecountrywasnotdiagnoseduntil1992.The increas-ing number of cases identified in Brazil show differences fromthediseasethatoccursintheNorthernHemisphere.21–24
In Brazil, the occurrence of Ixodes ticks (I. auritulus and I. loricatus) is associated with parasitism of some birds and
Didelphisalbiventris,25,26 whicharenotconsideredthe
prefer-entialvectorsforhorsesandhumans.Clinically,despitethe occurrenceofsignssuchaserythemamigransandtheusual systemiccomplications,theBraziliandiseaseprogresseswith recurrences, especially if antibiotic treatment is initiated later than three months after infection. Brazilian patients
have been reported to have a high frequency of antibod-iesagainstdifferentautologouscellcomponents.Therefore, BrazilianBorreliosis(BB)wasinitiallycalledLyme-likedisease, Lyme-likeborreliosisorBaggio-Yoshinarisyndrome(BYS)to distinguishitfromtheclassicaldisease.27
In addition, studies conducted in the Laboratory of Rheumatology of the Clinical Hospital of the School of Medicine,UniversityofSãoPaulo(LIM-17Hospitaldas Clíni-cas –Faculdade de Medicina, Universidade de São Paulo– FMUSP)showedtheoccurrenceofmicroorganismswith mor-phologicalstructuressimilar toMycoplasmaspp., Chlamydia
spp.,andnon-flagellatedspirochetesintheperipheralblood ofpatients with BYSwho were seropositivefor B. burgdor-ferisensu lato. However, those patients exhibited negative serologyforMycoplasmaspp.andChlamydiaspp.,suggesting amorphologicaldifferencebetweenB.burgdorferisensulato and the Brazilianmicroorganism identified as the possible causative agent ofBYS.28 Becausemotile and spiral
spiro-cheteswereneverisolatedorculturedinBrazil,researchers fromLIM-17assumedthattheetiologicalagentinBrazilwas presentincysticform.
Duetothesereasons,BBisdefinedasanemerging tick-bornedisease,differentfromLD,causedbyB.burgdorferisensu latowithatypicalmorphologiesandtransmittedbyticksnot belongingtoIxodes.ItispossiblethatBorreliabacterialpassage throughticksfromAmblyomma,Rhipicephalus,and Dermacen-torgeneracanresultinspirochetemorphologicandgenetic modificationsinbothvertebrateandinvertebratehosts,thus originatinganewdiseasesimilartoLD.28
BYSdiffersfromLDbecausethediseasehashigher mor-biditydue to the presenceof symptom recurrence, severe reactivemanifestationssuchasautoimmunity,andtheneed forprolongedtreatment.LaboratorydiagnosisofBYSis diffi-cultbecauseserologicaltests(ELISA,enzymeimmunosorbent assay,orwesternblotting)forB.burgdorferishowlow sensi-tivityand specificity27–32; this isbecausethesetests utilize
antigens from B. burgdorferi stricto sensu from the North-ernHemispheretoevaluateimmunoglobulinsofBrazilianB. burgdorferisensulato.
BYScancausesomesymptomssimilartothoseobserved inLD,includingerythemamigransinapproximately50%of patients,arthritisin35%,neurologicalsymptomsin35%,and cardiacdisease innearly5%.Thedisease isoften unrecog-nized,especiallyatsecondaryortertiarystageswhenpatients do not remember what occurred months or years before thecurrent disease.Certainly,many casesofunrecognized chronicneurologicalorarticulardiseaseareinfactcasesof BYSnotidentifiedandtreatedatearlystages.28
Thefirststudies inBrazil toreportthe occurrenceofB. burgdorferisensulatowerepublishedin2010,when dermatol-ogistsusedimmunohistochemistrytoidentifythespirochete inskinbiopsiesoftheerythemamigransfromfourpatients.33
Inasubsequentstudyemployingimmunohistochemistryand focusfloatingmicroscopy,Talhariandco-workers34also
iden-tifiedthebacteriuminskinlesionsfrom22patients.Despite conductingnested-PCR(polymerasechainreaction)using a setoffourprimers(externalprimers,1–AAGACGAAGATA CTCGATCTGTAATTGand2–TTGCAGAATTTGATAAAG TTGG,andinternalprimers,3–TCTGTAATTGCAGAAACA CCTand4–GAGTATGCTATTGATGAATTATTG),noneof
the22sampleswaspositive.Therefore,standardizingaPCR techniqueforidentificationoftheBorreliabacteriaoccurring inBrazilremainsachallenge.
Mantovaniandco-workers35 demonstratedthepresence
of spirochetes of genus Borrelia in the blood of human patients with BB by performing flgE gene amplification (470FW5-CGCCTATTCTAACTTGACCCGAAAT-3 and470Rev 5-TTAGTGTTCTTGAGCTTAGAGTTG-3) as well as in genus
Rhipicephalus ticks. Similarly, Gonc¸alves et al. identified B. burgdorferi s.l. strain B31 in D. nitens ticks collected on a horseinParanáState(nested-PCRtargetingthe 5S(rrf) 23S (rrl)intergenicspacerregion,99.9%BLASTsimilaritywithB. burgdorferis.s.).Additionally,thesameresearchgroup identi-fiedB.burgdorferisensulatointheblood ofhumansfroma rural areainParanáState(nested-PCRtargetingthe5S(rrf) 23S(rrl)intergenicspacerregion,100%BLASTsimilaritywith
B.burgdorferis.s.).36 However,phylogeneticanalysiswasnot
performedineitherstudy,leavingmanyuncertaintiesabout theclassificationoftheBrazilianpathogen(s).
Recentstudiesshowthepossibilityofticksofthegenera
AmblyommaandRhipicephalusbeingdirectlyrelatedto dissem-inationofthedisease.Rezendeandco-workers37reportedthat
embryonic cells ofR. microplus and A. sculptum (previously
cajennense according tothe newtaxonomic status38) could
serveassubstrateforthegrowthofB.burgdorferisensustricto strainG39/40.B.burgdorferisensulatowasidentifiedinA. amer-icanum tickscollected fromLDpatientsdiagnosedbyELISA andPCRinFlorida,USA.12
Borreliosis
in
horses
B.burgdorferisensulatoiscapableofinfectingwildand domes-tic animals. Additionally, domestic animals, such as dogs, cattle,andhorses,canbecarriersofthispathogen.Unlikethe unapparentdisease observedinwild animals,this etiologi-calagentiscapableofcausingclinicalsymptomsindomestic animals.39–42
Based on indirect ELISA and Western blotting, it was observed that horses exposed to ticks have a higher fre-quency of seropositivity for B. burgdorferi sensu lato than horsessubjectedtostricttickcontrol.43Inaddition,viable Bor-reliabacteriahavebeenfoundintheurineofhealthyhorses inanendemicregionoftheUnitedStates,44 warningofthe
possibilityagenttransmissionbycontactroutesinaddition totickbites.Changandco-workersvalidatedanequineLD modelbyexposingponiestoticksharboringB.burgdorferifor sevendays.Theythenevaluatedtheantibodyresponseand treatmentefficacyat120daysafterinfectionandfoundthat theantibodylevelsofthetreatedanimalsreturnedtonegative levelsin10months.45,46
In Brazil, it was detected an averageELISA seropositiv-ity of9.8%in horsesinthe state ofRiode Janeiro,and in the municipalityofSeropédica,thefrequencywas 42.8%.43
Madureira andco-workers47 observedafrequencyof28.4%
of anti-Borrelia homologous ELISA antibodies in horses in themunicipalitiesofTrêsRiosandVassouras,RiodeJaneiro State,whereasthefrequencywas26.7%inthemunicipalityof Belém,ParáState.48GuedesJuniorandco-workers49identified
dogs,therateofseropositivitywas48.25%inRiodeJaneiro city.50TheoccurrenceofLDinwildanimalveterinariansand
found6.4%seropositivity forB. burgdorferi s.l. inSãoPaulo city.51
Borreliosisinhorsesremainsunderdiagnosedandpoorly understoodbyveterinarians.Accordingtoasurveyconducted inGermanyof118veterinarians,only56%believethatLyme borreliosiscanaffecthorses.Whenaskedaboutthenumber ofanimalsdiagnosedinGermany,45%answeredthatno ani-malsarebeingdiagnosed.Regardingcontroloftheparasite, 46.5%statedthatownersrarelyperformectoparasitecontrol measures.Arelativelylargepercentageoftheveterinarians (30.5%)saidthat theywouldconfirm thediagnosis onlyby serologyandwouldnotperformserologicalmonitoringover time.Theyalsoindicatedthattheywouldtreatpositive ani-malswithantibioticsandanti-inflammatorymedication(54%) andstatedthat71%ofthehorseownersareunawareofthe disease.52
Studies indicate that LB in horses has clinical signs similar to the disease in humans,53 including fever and
lethargy,54 arthritis,55 polysynovitis,56 lameness, muscle
stiffness,57 abortion,54 meningitis, cranial neuritis,
radicu-loneuritisandencephalitis,58,59uveitis,55,60,61andpremature
deathoffoals.54
To study spirochete distribution in horses, Chang and co-workers experimentally infected eight ponies using I. scapularisticks infectedwithB.burgdorferi.Theponieswere euthanizedapproximatelyninemonthsafterinfection,and samples from several tissues, such as lymph nodes, skin, muscles,synovialcapsule,andmeninges,weresubjectedto moleculartestsusingprimerstargetingtheospAgeneandthe 23Sribosomalgeneaswellascellculture.B.burgdorferiwas mainlydetectedfromtheskin,fascia,andmuscle.45
Diagnosis
ThegoldstandardforlaboratorydiagnosisofLBis serologi-caltests(ELISAconfirmedbyWesternblotting).However,an increasingnumber ofstudies demonstrate thepotential of molecularandculturetestsasatoolfordiagnosis.Thefinal diagnosisinhumansisoftenbasedonsymptoms,exposure toticksandserologicaltests.62Formanyotherspeciesof
bac-teria,thegoldstandardforidentificationisculture.However,
Borreliaspeciescanonlygrowunderspecializedculture con-ditions,suchasBarbour-Stoenner-Kelly (BSK)mediumwith incubationat30◦Cto35◦Cforasmanyas12weeksunder microaerophilicconditions.IfaPCRmethodischosen,results obtainedfromskinbiopsiesfrompatientswithclassic ery-themamigransaremoresensitivethanaresamplesofblood collectedfromthesamepatients.63
ThelaboratorymethodsusedfordiagnosisofLBarethe fol-lowing:cultureinKellymediumofclinicalsamplesfromskin, cerebrospinalfluid,synovialfluid,andblood;molecular detec-tionusingtissuespecimens(targetingp66,16SrRNA,flagellar gene fla, 23S rRNA, and ospA genes and the 5S rRNA-23S rRNAintergenicspacerusingnestedorreal-timequantitative PCR);andantibodydetectionsuchasenzymeimmunoassays (ELISA), indirect immunofluorescentantibodyassays (IFAs), westernblotting,andpeptide-basedimmunoassays.64
Lymediseaseinhorsesmustbediagnosedbasedon(1)the possibilityofexposuretoticksinfectedwithB.burgdorferi,(2) clinicalsignscompatiblewithLD,(3)absenceofothercauses fortheclinicalsigns,and(4)ahightiterofanti-B.burgdorferi
antibodies.65Themostcommontechniqueusedfor diagnos-ingB.burgdorferiinhumansandhorsesisantibodydetection, and the mostfrequently usedtechniques are IFA,Western blotting,andELISA,withthelatterhavinggreater applicabil-ity forhorsesbecause itisfasterand cheaper.66 Specificity
testsforIFAand ELISAshow minimalcross-reactivitywith anti-Leptospiraantibodies.67,68Ingeneral,duetotheslow
mul-tiplicationofthespirochete inthe host,threetosixweeks may be required for detection of immunoglobulin G (IgG) titers, with eight to sixteen weeks needed to reach their maximum.43,45,46However,becausethespecificityofIFAand
ELISA tests is still questionable, a positive result must be confirmedbyaseconddiagnosticmethod.Westernblotting istypicallyusedtodetectantibodiesagainstBorrelia-specific
antigens69; alternatively, some researchers have used PCR,
whichhasthehighestsensitivityandspecificity.46,66
Chandrashekarandco-workersevaluatedthefeasibilityof usingacommercialenzymeimmunoassaykitdevelopedfor dogs(SNAP®4Dx)forthedetectionofanti-C6peptide
antibod-iesin160horsesinfectedbyB.burgdorferiandpreviouslytested bywesternblotting(QualiCodeTMIgG/IgMWesternBlotKits,
ImmuneticsInc.,Boston,MA).Thekitshowed100%specificity and95%sensitivitycomparedtothegoldstandardserological test,andtheauthorsindicatedthatthekitisarapidandsafe testforthediagnosisofborreliosisinhorsesinthefield.70
Asubsequentstudyfoundthatserologicaltestsusingan anti-C6commercialkit(SNAP®4Dx)couldidentifymostofthe
horsesinfected;however,italsoproducedfalsepositiveand falsenegativeresults.Inaddition,serologicaltestsfor detect-inganti-C6peptideantibodiesandOspCandOspF,whichare associatedwithclinicalsigns,werefoundtoconsistently sup-portthediagnosisofborreliosisinhorses.71
Equine
therapeutics
Treatmentwithoxytetracycline(6.6mg/kg,IV,every12h)for threeweekswasmoreeffectivethantheuseofdoxycycline (10mg/kg, VO, every 12h)or ceftiofur (2.2mg/kg, IM, every 12h).Oxytetracyclinewastheonlyantibioticthatledto neg-ativeresultsbothaccordingtocultureandtissuePCR(lymph nodes,skin,musclefascia,synovialmembranes,pericardium, andmeninges)attheendoftreatment.Oxytetracyclinecanbe administered(5.0mg/kg,IV,every 24h)forfourweeks,with highefficacyagainstB.burgdorferiinexperimentallyinfected ponies.46 Divers and co-workers found that tetracycline is
effectivefortreatingLBinnaturallyinfectedhorses(6.6mg/kg, IV,every24h).65
Final
remarks
LDisaconditionofextremeimportancebecauseitisa zoono-sisthatcausesphysicalandpsychologicalsequelaeinaffected individuals. It remains poorly investigatedin Brazil, espe-ciallyinthefieldofveterinarymedicine.Therefore, studies
describingtheuniqueaspectsofthediseaseinBrazilandthe etiologicalagentsfoundareneeded.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgement
TheauthorsacknowledgethefinancialsupportofFAPESP (Pro-cess2013/05871-0and2013/03732-0).
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