Will Mayaro virus be responsible for the next outbreak of an arthropod-borne virus in Brazil?

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w w w . e l s e v ie r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Review

article

Will

Mayaro

virus

be

responsible

for

the

outbreak

of

an

arthropod-borne

virus

in

Brazil?

Danillo

Lucas

Alves

Esposito,

Benedito

Antonio

Lopes

da

Fonseca

∗

UniversidadedeSãoPaulo,FaculdadedeMedicinadeRibeirãoPreto,DepartmentodeClínicaMédica,RibeirãoPreto,SP,Brazil

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Articlehistory:

Received20February2017 Accepted11June2017 Availableonline7July2017

Keywords: Mayarovirus Alphavirus Chikungunyavirus Epidemiology Outbreaks

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MayarovirusisanalphavirusfromtheTogaviridaefamilyandistransmittedmainlyby Hem-agogusmosquitoes.Thisviruscirculatesinhigh-densitytropicalforestsorruralareasof CentralandSouthAmericacausingadiseasecharacterizedbyhigh-gradefever, maculo-papularskinrashandmarkedarthralgiathat,insomepatients,canpersistforlongperiods afterinfectionandmaybemisinterpretedaschikungunya.Althoughonlyafewoutbreaks involvingthisvirushavebeenreported,inthelastyearsthenumberofMayarovirus infec-tionshasincreasedinthecentralandnorthernregionsofBrazil.Inthisreview,wedescribe thereportedprevalenceofthisinfectionovertheyearsanddiscussthecircumstancesthat cancontributetotheestablishmentofanurbanmayarovirusepidemicinBrazilandthe problemsencounteredwiththespeciﬁcdiagnosis,especiallytheantigeniccross-reactivity ofthispathogenwithothervirusesofthesamefamily.

Mayaro virus (MAYV; genus Alphavirus, family Togaviridae)

isanarbovirus transmittedprimarilybythe biteoffemale mosquitoesofthegenusHemagogus,usuallyfromaninfected non-humanprimate(monkeys)toasusceptiblehuman.These tree-dwellingmosquitoesarealsothevectorsinvolvedinthe sylvaticcycleofyellowfevervirus,andalthoughMAYV main-tenanceefﬁciencyinprimaryreservoirsisnotknown,ithas beendetectedinnatureinseveralvertebratehostssuchas non-humanprimates,rodents,birds,sloths,andothersmall mammals.1

Asforyellowfevervirus,MAYVcaninfecthumanswho inhabitthe rural areasor enterthese forestedareas either towork or to take advantageofthe environmental attrac-tions,leading to afebrile condition characterizedby fever,

∗ _{Corresponding}_author.

E-mailaddress:[email protected](B.A.Fonseca).

cutaneousrash,andjointpain.Inrecentyears,therehasbeen anincreasednumberofcasesofmayarofeverinseveral Brazil-ianstatesandwiththeincreasedcirculationofchikungunya virus,thereisalwaysaquestionastowhetherafebrile exan-thematousdisease withsevere joint involvementisdueto chikungunyaorMAYV.Inthisreview,basedonepidemiologic andlaboratorydata,wediscussthevariablesinvolvedinthe possibleestablishmentofoutbreakscausedbyMAYV.

The

virus

MAYV genome is composed of a single-stranded positive-sense RNA of approximately 12kb in size, ﬂanked by a

http://dx.doi.org/10.1016/j.bjid.2017.06.002

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Non-structural ORF

5’

m7_G CAP

nsP1

nsP2

nsP3

Stop codon Poli A Tail Poli A Tail C E3 E2 6K E1

nsP4

Structural genes

Structural subgenomic RNA

3’

3’ 5’ RNA translation RNA Translation Structural proteins Replication complex nsP1 nsP2 nsP3 nsP4 Read-through translation

Fig.1–AschematicMayarovirusgenomeorganizationanditsreplicationcomplex.

5-7-methylguanylate(m7_G)_cap_and_a₃_-poly-A_tail._It_encodes

fournonstructuralproteins(nsP1–4)andﬁvestructural pro-teins(C-E3-E2-6k-E1).2 _Similar_to_other _{alphaviruses,}_MAYV

RNA has a stop codon at the end ofnsP3 gene, and at a lowfrequency(5–20%),aread-throughtranslationcanoccur, resulting innsP1–4 product(Fig. 1). Structural proteinsare producedaftertranslationofasubgenomic RNAtranscript, synthesizedfromthenegative-senseRNAusedforreplication, acommonfeatureoftheTogaviridaefamily3 ₍_Fig.₁_).

Follow-ing the expressionof structuralproteins, the virus RNA is complexedtothecapsidproteinandtheenvelopeproteins, processedduringtheir trafﬁc throughthe Golgi apparatus, areinsertedintotheplasmamembranefromwherethevirus acquiresits envelope,releasing infectious particles able to infectsusceptiblecells.

Phylogenetically, MAYV is considered a monophyletic group,dividedintwosimilargenotypes–genotypeD,which includesmostoftheisolates,from1954to2003,and geno-typeL,limitedtotheBrazilianisolates.4_MAYV_is_part_of_the

SemlikiComplex,aserologicalgroupinsideAlphavirusgenus thatshares somecommon antigenicsites, which can gen-eratecross-reactivity with polyclonalimmune sera among thespecies,whenanalyzedbyconventionalserologicaltests, suchasHemagglutininInhibition(HI)andComplement Fixa-tion(CF).TheSemlikiComplexiscomposedbyeightviruses (Bebaru, Chikungunya,Mayaro, Getah, Semliki Forest, Ross River,O’nyong-nyong,andUnaviruses)ofveterinaryand med-icalimportance,usuallycausinghumandiseasecharacterized byfever,arthritisandskinrash5₍_Fig.₂_–_the_strain_of_MAYV

usedtoassemblethisphylogenywasBeAr202906_)._As

men-tionedbefore,thefactthatthesevirusesbelongtothesame serologicalcomplex,thecorrectdiagnosisoftheseinfections canbedifﬁculttoachieve,usuallyonlycarriedoutin well-equippedresearchlaboratories.Speciﬁcally,ofimportanceto Brazil,chikungunyaandmayarofevercanexhibitthesame clinicalmanifestationsandbothvirusesareco-circulatingin thecountry.

Clinical

manifestations

and

speciﬁc

diagnosis

Littleisknownabout thepathophysiology ofmayaro fever, butoncetheinfectionhasestablishedthevirusgoesthrough

anintrinsicincubationperiod,whichcanrangefrom3to11 days,whenahigh-ratereplicationtakesplacefollowedbya shortviremialastingwhilethesymptomsarepresent (usu-ally 5–7 days).The symptomsofMAYV infection are often an exanthematous rash, fever, myalgia, retro-orbital pain, headache,diarrhea,andarthralgia,thelattermaypersistfor monthsorevenyears.7_There_are_several_reports_on_the

litera-tureofpersistentorrecurrentarthralgiaresultingfromMAYV infection,8–10_which_could_be_a_result_of_an_inefﬁcient

neutral-izingantibodyresponseagainstthisvirusassociatedwiththe continuous expressionof some pro-inﬂammatory immune cytokines.11_However,_there_is_a_need_for_more_studies

evalu-atingthebroadspectrumoftheclinicalmanifestationsofthe acutephaseofthedisease,includingunusualpresentations, if present,aswellasthe possiblechronicclinical manifes-tations, and also, the viral and immunological parameters involvedinthecausationofeachformofthisdisease.

Asformostarboviralinfections,thediagnosisofalphavirus infection,suchasMayarofever,ismoreefﬁcientifperformed duringtheacutephaseofthedisease,eitherbyvirus isola-tionorRT-PCRtodetectviralRNA.Ataconvalescentphaseof infection,antibodycross-reactivityhasbeenshowntooccur whenusingtraditionalserologicaltests,suchasELISA.High cross-reactivitybetweenmayaroandchikungunyahasbeen described,12,13_and_either_side-by-side_tests_aiming_at_the

com-parisonofserumreactivitytoeachvirusorneutralizationtests shouldbeperformedtocorrectlyestablishthespeciﬁcityof anantibodyreaction,andprovideacorrectdiagnosisofthe disease.

Epidemiology

TheepidemiologichistoryofMAYVinfectionbeginsin1954 withitsﬁrstreportinTrinidadandTobago,whenthevirus wasisolatedfrombloodsamplesofﬁveruralworkersthat pre-sentedwithafebriledisease.Thevirusreceiveditsnameafter MayaroCounty,asoutheasternregionofTrinidad,wherethe caseswerereported.14_Since_then,_the_virus_has_been_reported

insomecountriesinCentralandSouthAmerica,usuallyin placeswithtropicalforests,suchasFrenchGuiana,Bolivia, Peru, Suriname, CostaRica,Guatemala, Venezuela,Mexico, Ecuador,Guyana,Panama,andBrazil.Importedcasesarenot veryfrequent,butsomehavebeenreported:NorthAmericans

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gb|L01442.2|Venezuelan equine encephalitis virus gb|AF075251.1| Everglades virus Fe3-7c strain

gb|AF075259.1| Venezuelan equine encephalitis Cabassou strain gb|AF075253.1| Mucambo virus BeAn8 strain

gb|AF075256.1| Pixuna virus BeAr 35645 strain

gb|AY722102.1| Eastern equine encephalitis virus PE6 strain gb|HM147991.1| Trocara virus

ref|NC 003900.1| Aura virus ref|NC 016961.1| Whataroa virus ref|NC 001547.1| Sindbis virus gb|HM147984.1| Babanki virus gb|M69205.1| Ockelbo virus Edsbyn strain ref|NC 001786.1| Barmah Forest virus gb|JX644166.1| Ndumu virus BAR S2 3526 strain gb|KF680222.1| Middelburg virus SAE25 11 strain

gb|AF369024.2| Chikungunya virus strain S27-African prototype gb|M20303.1|ONyong-nyong virus Gulu strain

ref|NC 003215.1| Semliki forest virus

ref|NC 016962.1| Bebaru virus

gb|GQ433359.1| Ross River virus T48 strain

gb|KT754168.1| Mayaro virus BeAr20290 strain - Genotype L KP842809.1 Mayaro virus BeH186258 strain - Genotype D

Semliki comple x 0.0538 0.0663 0.1655 0.1496 0.1031 0.0454 0.1463 0.2501 0.0395 0.3085 0.2525 0.1674 0.0256 0.0146 0.0156 0.0163 0.1465 0.1015 0.3059 0.2806 0.2429 0.1758 0.1226 0.1390 0.0717 0.0659 0.2230 0.1771 0.2305 0.0462 0.0393 0.1876 0.0441 0.0506 0.0630 0.0577 0.0329 0.0984 0.0828 0.1105 0.0451 0.1583

Fig.2–MolecularphylogeneticanalysisofsomeclinicallyimportantalphavirusesusingMaximumLikelihoodmethod.A representativestrainofeachspecies,withacompletegenomedepositedatNCBIwebsite,wasusedtoconstructthe phylogenetictree.Atotalof9946positionswereanalyzedintheﬁnaldataset.Thenumbersabovebranchesindicatethe evolutionarydistance(branchlength).EvolutionaryanalyseswereconductedusingMEGA7software.Thestrainsofmayaro virususedtoassemblethisphylogenywereBeAr20290(5)_for_genotype_L_and_BeH186258_for_genotype_D.

visitingPeru15 _and_Bolivia10_;_French_citizens_returning_from

French Guiana16 _and _Brazil17_; _a _German _woman _returning

fromBolivia18_;_a_Swiss_tourist_visiting _Peru19_;_a_Dutch

cou-plereturningfromSuriname,20_and_some_interstate_imported

casesinBrazil.21,22_The_virus_is_considered_endemic_in_some

placesofBrazil,suchasthenorthern,central,andwestern regionsofthecountry.TheﬁrstcaseinBrazilwasreportedin 195523_next_to_Guama_River,_Pará_state,_and_the_ﬁrst_epidemic

inBraziloccurredinavillagenexttothatriver.Alittlemore thantwodecadesafterthat,in1978inBelterra,Pará,an out-breakwasdescribedwith55conﬁrmedcases(43withvirus isolationand12withserologicaltests)fromatotalof72 indi-vidualswithacuteillness(feverandarthralgiawerepresent inmostofthem).24

Othertwooutbreaks havebeenreportedbyVasconcelos etal.25 _in_Conceic¸ão_do_Araguaia _in₁₉₈₁_and_Benevides _in

1991,bothcitiesinParástate,northernBrazil,andinPeixe, Tocantinsstatein1991.Inthebeginningof2008,anoutbreak broke out ina settlementin Santa Barbara and surround-ings,Parástate.Fromatotalof105individualsthatreported afebrileconditioninthepast30days,36hadIgMantibodies againstMAYV.26_It_was_reported_the_presence_of_IgM_antibodies

againstMAYVin33patients,andviralgenomewasdetected fromoneoftheminManaus,duringanacutefebrileoutbreak in2007–2008.27_Also,_during_a_dengue_virus_outbreak_in_Mato

Grosso,Central-WestregionofBrazil,15outof604patients werepositiveformayaroRNAdetectionduringanacutefebrile illness.28

Morerecently,thestateofGoiásexperiencedanother out-breakofthedisease,andabout183caseshavebeennotiﬁed. From December2014untilJanuary2016,atotalof343 sus-pectedcaseswerenotiﬁedasaresultofMAYVinfectionin Brazil,inwhichmorethan50%werefromGoiásState.29_Some

ofthosecaseswereinitiallyreportedaschikungunya infec-tion,sincebothvirusesarecloselyrelatedtoeachotherand thereisantibodycross-reactivityintheavailablediagnostic tests. Asanevidenceforthiscross-reactivity, alarge num-berofmayarofevercasesthatoccurredinthisoutbreakwere positiveforbothvirusesbyserologictests.

Theincreasingincidenceofmayarofeverinregionsofthe country other than thenorthernregion, wherethe disease isendemic,isagrowingconcern becausethiscan indicate thatthevirusisspreadingtootherpartsofthecountry,and futureepidemicsmayoccurinBrazil,inareaswherehealth careworkersarenotfamiliarwithmayarofeverclinical pre-sentation.

Laboratory

studies

Evidence thatmosquitoesfrom genusAedescouldtransmit MAYV is another circumstance thatmay contributeto the establishmentofmayarofeveroutbreaksinBrazil,sincemost of the country is infestedby both Aedes aegypti and Aedes albopictus.Laboratoryexperimentshaveshownthat,indeed, MAYVcaninfectAe.albopictus,determiningaproductiveviral

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replicationnotonlyinvitro,butinvivo,andthen,transmitthe virus.30,31 _Similar_to_Ae._albopictus,_Ae._aegypti_showed _to_be

aneffectivevectortotransmitMAYV.Afterlaboratory infec-tionofmosquitoes,theviruscouldbefoundinthesalivary glandsand could besuccessfullytransmittedtomice, ata highrateofinfection.32_In_addition_to_laboratory_infection_of AedesmosquitoesbyMAYV,Serraetal.33_found_{MAYV-infected} Ae.aegyptiandCulexquinquefasciatusintheirnaturalhabitats, inCuiabá,MatoGrosso,Brazil.Alltheseﬁndingsunderscore thepossibilityofMAYVinfectionofAedessp.mosquitoesand thetransmissioncycleofthisvirusmayshiftfromsylvaticto urban,usinghumansasamplifyinghosts,andthen establish-ingnewoutbreaksinBrazil,sincethemajorityoftheBrazilian populationissusceptibletoMAYVinfection.

Prevention

and

control

of

MAYV

infections

ThereisnoantiviralagainstMAYVandonlysymptomsare treated,similartotreatmentavailableforchikungunyavirus infection,withthe initialprescription ofnonsteroidal anti-inﬂammatorydrugsandanalgesicsforpainandfeverrelief, andsometimescorticosteroids,althoughitsefﬁcacyhasnot beenfullyproven.34_Not_much_data_is_available_on_MAYV

treat-ment,but drugsandtherapiesareadministratedsimilar to otheralphavirusinfectionsthathaveaclinicalcourse compa-rabletomayaroinfection,suchaschikungunyaandRossRiver viruses.

Nocommercialvaccinesareavailable,buttwocandidates weretestedinpre-clinicalexperiments.Theﬁrstattempt gen-erated inactivated particles, using different concentrations offormalinandshowedtobeimmunogenicwhen adminis-tratedinmouse,withsomeefﬁcacy.35_Another_candidate_was

aliveattenuated vaccine,thatcould replicateinvertebrate cells,butnotinmosquitoes,withmutationsinsub-genomic promoterandtranslationalcontrolofaninternalribosomal site (IRES) from encephalomyocarditisvirus (EMCV),which demonstratedagreatproductionofneutralizingantibodies andahighrateofsurvivalafterchallenge,using immunocom-petentmice.36

Conclusion

MAYVisthecause ofanemergentinfection inCentraland SouthAmerica,and similarto whathappenedtozika and chikungunyaviruses,ithasthepotentialtoestablishan epi-demicscenario inBrazil.Although thereis noevidence of thetransmissionefﬁciencyofMAYVinanurbancycle,the susceptibilityofthepopulationtothisinfection,inaddition tothe possibilityoftransmissionofthispathogen byAedes

mosquitoes, widely distributed in Brazil, can increase the numberofinfectedindividuals.Duetoitsantigenicsimilarity withchikungunyavirus,itiscleartheurgencyforthe develop-mentofspecificandaccuratediagnosticmethodsforabetter diagnosisofMAYVinfections.Inthepossessionofaccurate diagnostictests,itwillbepossibletodistinguishtheinfections causedbyMAYVfromother arboviralinfections anddefine therealimportanceofMAYVtothe Brazilianpublichealth andtodefine thecompletepicture ofmayarofeverclinical manifestations.

Since2014,agrowingepidemicofchikungunyavirus infec-tion isoccurringinBrazil.Datafrom theBrazilianMinistry ofHealthshowalmosta10-foldincreaseofsuspectedcases occurred inBrazil,fromthe yearof2015to2016(38,499to 265,554 cases,respectively),37 _with_most_of_the _cases_being

reported in the northern and northeastern regions of the country,whereMAYVisendemic.Mostofthesecaseswere diagnosedbyaclinical–epidemiologicalcriterion,sincethere are no reliableand speciﬁcserologicalteststoconﬁrm the infection. Considering that no difference can be found in symptoms from both infections, the number of cases of mayaro fever could be underestimated and many of the chikungunyacaseswerereallyMAYVinfections.

Interms ofcontrollingpossiblemayarofeveroutbreaks, sincethereisnovaccinetosuppressthespreadofthis dis-ease, theonlycurrentapproachisvector control.However, this approach has proved so far inefﬁcient, inthe view of the increasingnumber ofnewarboviralinfections (dengue, zika, chikungunya,and evenmayaro)inthecountry inthe lastyears.Finally,inordertolowertheimportanceofthese diseases to public health, it is of paramount importance the development ofa vaccine or anantiviral treatment to alphavirusinfections,duetotheimpactmayaroand chikun-gunyafevermayhaveonthequalityoflifeofpeopleinfected withtheseviruses.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

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