JPediatr(RioJ).2017;93(6):548---550
www.jped.com.br
EDITORIAL
Maternal
immunity,
a
way
to
confer
protection
against
enteropathogenic
Escherichia
coli
夽
,
夽夽
Imunidade
materna,
uma
forma
de
conferir
protec
¸ão
contra
Escherichia
coli
enteropatogênica
Alfredo
G.
Torres
a,baUniversityofTexasMedicalBranch,DepartmentofPathology,Galveston,UnitedStates
bUniversityofTexasMedicalBranch,DepartmentofMicrobiologyandImmunology,Galveston,UnitedStates
Diarrheal diseases caused by Escherichia coli remain as important causes of morbidity and mortality worldwide; children inthe developing world suffer the majorburden ofdiarrhealillnesses,whiletheburdenamongchildrenand adultsinthedevelopedworldismoreevenlydistributed.1
At least six different E. coli pathovars have been associ-ated withdiarrhealdisease, andeach one usesa distinct collectionofvirulencefactorstosubverthostcellular func-tions and potentiate their virulence, resulting in distinct clinicalmanifestations.2,3Oneoftheoldestandbetter
char-acterized diarrheal pathovars is enteropathogenic E. coli
(EPEC),whichencompassagroupofisolatesthatarea sig-nificantcauseofpersistentwaterydiarrheaamongchildren worldwide.4 EPEC isolates belong to a limited number of
O:Hserotypes, andareknowntocarry thelocusof ente-rocyte effacement (LEE), a region that encodes several proteinsmediatingthe interactionwiththehost cellsand theformation of adistinct lesion knownasattachingand
DOIoforiginalarticle:
http://dx.doi.org/10.1016/j.jped.2016.12.005
夽
Pleasecitethisarticleas:TorresAG.Maternalimmunity,away toconferprotectionagainstenteropathogenicEscherichiacoli. J Pediatr(RioJ).2017;93:548---50.
夽夽
SeepaperbyAltmanetal.inpages568---75. E-mail:[email protected]
effacing(A/E).2Moreover,EPECstrainsmaycontaina
viru-lenceplasmidcalledEPECadherencefactor(EAF),because it encodes gene products involved in the synthesis and assemblyofthebundle-formingtypeIVpilus(bfp),andalso lacksthegenesencodingforShiga toxin(stx)production.2
The pEAFplasmid isusedtosub-classify thesestrainsinto typical EPEC (tEPEC; thosethat areLEE+/stx−/bfp+) and
atypicalEPEC(aEPEC;thosewhichareLEE+/stx−/bfp−).5,6
In contrast, the related pathovar enterohemorrhagic
E. coli(EHEC) possess thegenotype LEE+/stx+/bfp−, and
production of stx is associated with further systemic complications.2
Tothisday,EPECcontinuestoberesponsiblefor5%---10% of pediatric diarrhea in developing countries; however, it isreportedthatthefrequencyofEPEC(particularlytEPEC) infections drops with age, and therefore adults rarely experience tEPEC episodes.5,7 Interestingly, infant acute
diarrheal episodes caused by tEPEC have been declining throughout the years in many countries, including Latin America andEurope.4,8 Moreover,alarge studyconducted
inseveralcountriesinAfricaandAsiabytheGlobalEnteric MulticenterStudy(GEMS)networkdemonstratedthattEPEC strains were not among the leading pathogens causing acutemoderateandseverediarrheainthesegeographical regions.9However,tEPECinfectionappearstobeassociated
witha2.8-foldincreasedriskofdeathamonginfantsaged 0---11months.9 Incontrast,aEPECcontinuestobeisolated
http://dx.doi.org/10.1016/j.jped.2017.05.002
MaternalimmunityagainstEPEC 549
in both developing and developed countries; in some countries,theyhavesurpassedtEPECinfections.4,10Insome
studiesfromdevelopingcountries,itwasdemonstratedthat aEPECisolates wereresponsible for78% of allEPEC cases inchildren agedless than5years.7 Regardlessof whether
tEPECoraEPECareresponsibleforthediarrhealepisodesor thegeographicdistributionoftheisolates,itisclearly evi-dentthatEPECisolatesarestillamongthemostimportant pathogens causingdiarrhea.5,6,10 Thus, thereis aneed for
atherapeutic intervention toreducethe numberof cases worldwide.
Ideally, themost effective waytoprotectinfants from EPEC infectionis by antibodies acquisition through active orpassiveimmunization.Severalstudieshavestrongly sug-gestedthatbreastfeedingmightbeabletoprotectinfants againstEPECduetothepresenceofantibodiesdirectedto specificEPECvirulencefactors.11---15Therehavebeenseveral
reports of antibodies againstvarious secreted or surface-locatedEPECvirulencefactors,includingthoseencodedon the LEE pathogenicity island or the virulence pEAF plas-mid, which can bind these factors and potentially block bacterialcolonization.2,5,11---15Fromthoseimmunogenic
pro-teins, a key virulence factor is intimin, the main EPEC and EHEC membrane-located adhesin, which is encoded by the eae gene within the LEE pathogenicity island.2
Several different types of intimins have been reported basedonthepolymorphismswithintheirC-terminalregion (knownas Int280) and themost frequently found are the
␣, , and ␥ types.2,15 The distribution of these intimin
proteins is associated with different EPECand EHEC evo-lutionary lineages. Intimin ␣ is found within the EPEC lineage known as EPEC-1; intimin  is distributed among human and animal pathogens, including EPEC-2, EHEC-2, and Citrobacter rodentium; whereas intimin ␥ is asso-ciated with EHEC O157:H7 and aEPEC strains.8 It has
beenpreviously shownthathumanimmunoglobulins (e.g., secretory IgA) from breast milk can inhibit EPEC local-ized adherence to cultured cells in vitro and that these immunoglobulinsarealsoabletorecognizedifferentintimin proteins.11---15
Epidemiological studies in Brazil16 have elucidated a
quite unique map for the distribution of EPEC pathovars, confirming theprevalenceof thesepathogenic E.coli iso-lates and reinforcing the fact that aEPEC strains have replaced tEPEC as the most prevalent EPEC subclass associated withhuman disease in this country.17
Interest-ingly, early acquisition of antibodies against intimin by healthyBrazilianchildrenlivinginendemicareashasbeen demonstrated,14suggesting thatthoseantibodiesmightbe
responsibleforprotectionagainstthepathogen.Moreover, it has been found that serumIgG andsecretory IgA anti-bodiesarereactiveagainstconservedandvariableregions of the intimins ␣, , and ␥; the cross-reactivity among anti-intiminantibodieshasalsobeendemonstrated.15These
studiessuggestacorrelationbetweentheconcentrationof theantibodiesinbothserumandcolostrumandthe proba-bleprotectionelicitedinchildrenreceivingtheseantibodies
viabreastfeeding.Furthermore,thecross-reactivityofthe antibodies withdifferent intimins suggest thatit is possi-bletoprotectagainstdifferentA/E-producingE.coli(e.g., EPECorEHEC).15
InarecentstudypublishedintheJornaldePediatria, Alt-manetal.investigatedthetransferofmaternalanti-intimin antibodiesfromhealthyBrazilianmotherstotheirnewborns throughtheplacentaandcolostrum,andfoundavariability in the concentrations of theseantibodies.18 The
antibod-ies displayed differential reactivity to different types of intiminsaswellastothedifferent(conservedandvariable) regionsoftheintimins␣,,and␥.Interestingly,the inves-tigatorsfoundthatIgGserumantibodies,reactivetoallthe intiminsubtypes, were transferred tothe newborns, and thatthe antibody concentrations varieddepending of the structuralregionof the intiminprotein tested (conserved
vs. variable).18 This study has significant implications for
thedevelopmentofapotentialtreatmentbecausein addi-tionof demonstrating that anti-intimin antibodies can be transferredfrommotherstonewbornsthroughtheplacenta, reinforcing the importance of passive immune protection againstpathogenicE.coli,itopensthedoorforthe devel-opment of other immunization approaches to effectively combatthesepathogens.
Because EPEC and other A/E-producing E. coli require multiplevirulencefactorstocausedisease,in additionto the intimin protein, it might be feasible to propose the developmentofavaccinethattargetsmultipleEPEC/EHEC antigenic epitopes and which is administered to expect-ingmothers.Ifmaternal antibodies aregeneratedagainst differentE. coli antigens and can betransferred to new-borns,thenthistypeofvaccineshouldbethenextpriority tocombatpediatric diarrhealdisease.10 Inthe past,EPEC
hasalsobeenthetargetfordevelopmentofcattleimmune milk.19Initialeffortsusingmilkimmunoglobulinconcentrate
containing antibodies to different EPEC strains, prepared byhyper-immunizationofpregnantcows,andusedtotreat infantswithgastroenteritis,resultedinover80%ofchildren testingnegativeintheirstoolsfordifferentEPECisolates.19
This approach, as well as the study by Altman et al.,18
provide evidence that treatment with specific antibodies foundinmilkshouldbefurtherexploredasaneffectiveway toeliminateorpreventEPECcolonizationoftheintestine.
Conflicts
of
interest
Theauthordeclaresnoconflictsofinterest.
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