Titre De La Thèse: Analyse Des Facteurs Influençant L'acquisition De L'immunité Anti-Pfemp1

Titre de la thèse:Analyse des facteurs influençant l'acquisition de l'immunité anti-Pfemp1 chez le jeune enfant

Name: MOUSSILIOU Azizath

E-mail:

Home institution adress: Laboratoire de biochimie et de biologie moléculaire 01 BP 918 Cotonou Bénin

Host institutionadress: Laboratoire de parasitologie 4 avenue de l’Observatoire 75006 Paris France

Abstract

This workaimed to characterize the burden of P. falciparuminfections duringpregnancy and to study the construction of the anti-PfEMP1 immunity in the early life.

The first part of the manuscript reportsstudieson the impact of malaria infection on pregnancyoutcomesand the effectiveness of preventivetreatments in the mother. Thesestudieswereconducted on a cohort of 1037 womenenrolled ina prospective study in Beninfrom 2008 to 2011. The results of thisgenerated show thatsubmicroscopic infections thatevadeconventionaldetectionmethods (microscopy, RDTs) drive the sameconsequences for the mother (anemia) and fetus (intrauterinegrowth restriction). The impact of theselow-density infections on maternalhemoglobinwasdemonstratedthroughout the pregnancy. Currentmethod of malaria preventionduringpregnancyby the ITP-SP, has shownitsinability to effectivelyclearinfectedpregnantwomen of their parasite. Major recurrent and recrudescences of infections by persistent low-densityparasitemia have been described. Sincesuchlow-densityparasitemiaremain a real problem for the mother and the child in the context of pregnancy, ourresultsfurther support the need to find alternative strategy of preventionthatprovidesbettercoverage of the entireperiod of pregnancy.In the second part of thethesis, westudied the construction of anti-PfEMP1 immunity in the first year of life in childrenwhosemotherswerefollowedduringpregnancy. This studywhich for the first time has characterized the passivelytransferred anti-PfEMP1 IgGfrom the mother to herfetus, has alsoanalyzed the dynamics of the acquisition of anti-PfEMP1 antibodyspecificallytargetingtheregionsinvolvedin the interaction withvariousreceptorssuch asCD36, EPCR and the phenomenon of rosetting up to 12 months of age of the child. A major finding of thisstudyis the demonstrationthat the acquisition of antibodiesagainst the PfEMP1 associatedwith complications of malaria (specific for EPCR and rosettes) isdependent to patent infections in children. This suggestsindirectly the major implication of these PfEMP1 variants in clinicalforms of malaria whilePfEMP1 withspecificity for CD36 are mainlyexpressed by the less virulent parasites.

The last part of the thesisparticularlyfocusedon the characterization ofparasitephenotypesfromvariousclinicalforms of malaria in Benineesechildren. Samplesfromchildrenaged 0-5 years have wereanalyzed to highlightelevated plasma levels of sEPCRon admission as a marker of poorprognosis of cerebral malaria. On a second component, weshowedthat the parasites responsible for cerebral malaria highlytranscribevargenesencoding PfEMP1 containing DC13 whileisolatesadheringhighly to ICAM-1, highlytranscribed the genesencoding PfEMP1 containing DC8. Theseresultsraise the question of the role of differentreceptorsidentified to date and particularly EPCR in the pathophysiology of cerebral malaria, and suggests theexistence of a cascade of interactioneventsthatoccurin the pathophysiologyof cerebral malaria.

Theworkdevelopedin thisthesis hasallowed to describefor the first timethe construction of theanti-PfEMP1 immunity inthe firstyear of life,has helpedupdateknowledge onthe pathophysiologyof cerebral malariain youngchildrenand identifiedavenues of primarily explorationin the perspective ofdeveloping a vaccineagainstsevereformsof malaria.