Structure-guided identification of a family of dual receptor-binding PfEMP1 that is associated with cerebral malaria

Cerebral malaria is a deadly outcome of infection by Plasmodium falciparum, occurring when parasite-infected erythrocytes accumulate in the brain. These erythrocytes display parasite proteins of the PfEMP1 family that bind various endothelial receptors. Despite the importance of cerebral malaria, a binding phenotype linked to its symptoms has not been identified. Here, we used structural biology to determine how a group of PfEMP1 proteins interacts with intercellular adhesion molecule 1 (ICAM-1), allowing us to predict binders from a specific sequence motif alone. Analysis of multiple Plasmodium falciparum genomes showed that ICAM-1-binding PfEMP1s also interact with endothelial protein C receptor (EPCR), allowing infected erythrocytes to synergistically bind both receptors. Expression of these PfEMP1s, predicted to bind both ICAM-1 and EPCR, is associated with increased risk of developing cerebral malaria. This study therefore reveals an important PfEMP1-binding phenotype that could be targeted as part of a strategy to prevent cerebral malaria

Asymptomatic Carriage of Plasmodium in Urban Dakar: The Risk of Malaria Should Not Be Underestimated

Introduction: The objective of this study was to measure the rate of asymptomatic carriage of plasmodium in the Dakar region two years after the implementation of new strategies in clinical malaria management. Methodology: Between October and December 2008, 2952 households selected in 50 sites of Dakar area, were visited for interviews and blood sampling. Giemsa-stained thick blood smears (TBS) were performed for microscopy in asymptomatic adult women and children aged 2 to 10 years. To ensure the quality of the microscopy, we performed a polymerase chai

Plasmodium falciparum malaria in pregnancy and childhood : molecular and immunological caracterization

Ce travail avait pour objectif, de caractériser le poids des infections au cours de la grossesse et d’étudier la construction de l’immunité anti-PfEMP1 chez le jeune enfant. La première partie, aborde la conséquence des infections et l’efficacité des traitements chez la mère. Cette étude réalisée sur la cohorte de femmes d’une étude prospective au Bénin, a démontré l’impact des infections à bas bruit sur le taux d’hémoglobine maternel et le faible poids de l’enfant. Le TPI-SP, a montré les limites quant à sa capacité à débarrasser les femmes enceintes infectées au moment du traitement de leur parasite. Nos résultats soutiennent davantage la nécessité de trouver des moyens alternatifs de prévention qui offrent une meilleure couverture de la grossesse. La deuxième partie aborde la construction de l’immunité anti-PfEMP1 dans la première année de vie chez l’enfant. Un résultat majeur de cette étude est la démonstration que l’acquisition des anticorps contre les PfEMP1 associés aux complications du paludisme est dépendante des infections patentes de l’enfant. La troisième partie aborde les phénotypes des parasites responsables de diverses formes cliniques du paludisme chez l’enfant Africain âgé de 0 à 5 ans. Cette étude a permis de mettre en évidence un marqueur de mauvais pronostic du paludisme cérébral. Sur un deuxième volet, nous avions montré que les isolats adhérant faiblement à ICAM-1, transcrivent fortement les gènes codant pour les PfEMP1 contenant des motifs DC8. Ces résultats soulèvent la question du rôle de EPCR dans la physiopathologie du neuropaludisme. Le travail développé dans cette thèse a permis de décrire pour la première fois la construction de l’immunité anti-PfEMP1 dans la première année de vie, de mettre à jour les connaissances sur la physiopathologie du paludisme cérébral chez le jeune enfant et de dégager des pistes à explorer prioritairement dans la perspective du développement d'un vaccin contre les formes graves du paludisme.This work aimed to characterize the burden of P. falciparum infections during pregnancy and to study the construction of the anti-PfEMP1 immunity in the early life. The first part discusses the consequence of infection and the effectiveness of treatments in the mother. This study on the cohort of women from a prospective study in Benin, demonstrated the impact of infections with low parasitemia on the maternal hemoglobin and low weight of the child. IPT-SP, has shown the limits of its ability to rid infected pregnant women in the processing of their parasite. Our results further support the need to find alternative means of prevention that provide better coverage of pregnancy. The second part treated the construction of the anti-PfEMP1 immunity in the first year of life in children. A major finding of this study is the demonstration that the acquisition of antibodies against the PfEMP1 associated with complications of malaria depends on patentes infections in children. The third part studies parasites phenotypes responsible of various clinical forms of malaria in African children aged 0-5 years. This study allowed finding a marker of poor prognosis of cerebral malaria. On a second component, we showed that isolates bind to ICAM-1, highly transcribe the genes encoding PfEMP1 containing DC8. These results raise the question of the role of EPCR in the pathophysiology of cerebral malaria. The work developed in this thesis has allowed describing for the first time the construction of the anti-PfEMP1 immunity in the first year of life, to update knowledge on the pathophysiology of cerebral malaria in young children and identify Options to be primarily from the perspective of developing a vaccine against severe forms of malaria

Le paludisme et l'immunité anti palustre chez le jeune enfant, cas du projet ISAMIMA

International audienc

Absolute and relative quantification of <i>Plasmodium</i> DNA in mosquitoes.

<p>This figure shows a not significant difference was observed in the <i>P. falciparum</i> densities between the two <i>Anopheles</i> species (P-value = 0, 2197).</p

Figure 1

<p>Transcription level of <i>var</i> genes were shown as relative copy number. Bars indicate the median of distribution.</p

Prevalence of co-infection of <i>Plasmodium spp</i> in mosquitoes (<i>An. gambiae</i> and <i>An. funestus</i>) by Real-time PCR.

<p>The figure (A) shows results of speciation analysis of 43 positive samples of <i>An. gambiae</i> ss by qPCR. Of the 43 positive samples, 35 were infected by <i>P. falciparum</i> only (81%), 7 samples showed mixed infection with <i>P. falciparum</i> and <i>P. malariae</i> (16%), and a mixed infection with <i>P. falciparum</i> and <i>P.ovale</i> was observed in 1 sample (2%). The figure (B) shows results of analysis of 22 positive samples of <i>An. gambiae</i> ss by qPCR. Among the 22 positive samples, mono infection with <i>P. falciparum</i> was found in 19 samples (86%), 1 sample showed mixed infection with <i>P. falciparum</i> and <i>P. malariae</i> (4.5%), mixed infection with <i>P. falciparum</i> and <i>P. ovale</i> was observed in 1 sample (4.5%), and in 1 sample mixed infection with 3 species (<i>P. falciparum</i>, <i>P. malariae</i> and <i>P. ovale)</i> was noted (4. 5%).</p

Specific detection of <i>Plasmodium</i> DNA by real-time PCR in the artificial target mixtures.

<p>Footnote: Validation of real-time PCR on artificial mixed targets. Plasmids constructs are: Pf, Po and Pm for <i>P. falciparum, P. ovale</i> and <i>P. malariae</i> respectively. Corresponding detection systems primers/probe are shown as FAL, MAL, OVA and Plasmo. Data are cycle threshold (Ct) values.</p