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Age-dependent increase in antibodies that inhibit Plasmodium falciparum adhesion to a subset of endothelial receptors.

ABSTRACT: BACKGROUND:Plasmodium falciparum-infected erythrocytes (IE) sequester in deep vascular beds where their adhesion is mediated by an array of endothelial surface receptors. Because parasite adhesion has been associated with disease, antibodies that block this activity may confer protective immunity. Here, levels of plasma anti-adhesion activity and surface reactivity against freshly collected IEs from malaria-infected children were measured in a Malian birth cohort and related to child age and malaria infection history. METHODS:Plasma samples from children enrolled at birth in a longitudinal cohort study of mother-infant pairs in Ouelessebougou, Mali were collected at multiple time points during follow-up visits. Anti-adhesion antibodies (i.e., inhibit IE binding to any of several endothelial receptors) and reactivity with surface IE proteins were measured using a binding inhibition assay and by flow cytometry, respectively. RESULTS:Levels of antibodies that inhibit the binding of children's IE to the receptors ICAM-1, integrin ?3?1 and laminin increased with age. The breadth of antibodies that inhibit ICAM-1 and laminin adhesion (defined as the proportion of IE isolates whose binding was reduced by???50%) also significantly increased with age. The number of malaria infections prior to plasma collection was associated with levels of plasma reactivity to IE surface proteins, but not levels of anti-adhesion activity. CONCLUSIONS:Age is associated with increased levels of antibodies that reduce adhesion of children's IE to three of the ten endothelial receptors evaluated here. These results suggest that anti-adhesion antibodies to some but not all endothelial receptors are acquired during the first few years of life.

SUBMITTER: Attaher O

PROVIDER: S-EPMC6458601 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Age-dependent increase in antibodies that inhibit Plasmodium falciparum adhesion to a subset of endothelial receptors.

Attaher Oumar O Mahamar Almahamoudou A Swihart Bruce B Barry Amadou A Diarra Bacary S BS Kanoute Moussa B MB Dembele Adama B AB Keita Sekouba S Gaoussou Santara S Issiaka Djibrilla D Dicko Alassane A Duffy Patrick E PE Fried Michal M

Malaria journal 20190411 1

<h4>Background</h4>Plasmodium falciparum-infected erythrocytes (IE) sequester in deep vascular beds where their adhesion is mediated by an array of endothelial surface receptors. Because parasite adhesion has been associated with disease, antibodies that block this activity may confer protective immunity. Here, levels of plasma anti-adhesion activity and surface reactivity against freshly collected IEs from malaria-infected children were measured in a Malian birth cohort and related to child age ...[more]

PMID: 30971252

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Project description:Plasmodium falciparum malaria remains one of the world's leading causes of human suffering and poverty. Each year, the disease takes 1-3 million lives, mainly in sub-Saharan Africa. The adhesion of infected erythrocytes (IEs) to vascular endothelium or placenta is the key event in the pathogenesis of severe P. falciparum infection. In pregnant women, the parasites express a single and unique member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family named VAR2CSA, which is associated with the ability of the IEs to adhere specifically to chondroitin sulphate A (CSA) in the placenta. Several Duffy-binding-like domains from VAR2CSA molecules have been shown in vitro to bind to CSA, but it has also been demonstrated that Duffy-binding-like domains from PfEMP1 proteins other than VAR2CSA can bind CSA. In addition, the specificity of the binding of VAR2CSA domains to glycosaminoglycans does not match that of VAR2CSA-expressing IEs. This has led to speculation that the domains of native VAR2CSA need to come together to form a specific binding site or that VAR2CSA might bind to CSA through a bridging molecule. Here, we describe the expression and purification of the complete extracellular region of VAR2CSA secreted at high yields from insect cells. Using surface plasmon resonance, we demonstrate that VAR2CSA alone binds with nanomolar affinity to human chondroitin sulphate proteoglycan and with significantly weaker affinity to other glycosaminoglycans, showing a specificity similar to that observed for IEs. Antibodies raised against full-length VAR2CSA completely inhibit recombinant VAR2CSA binding, as well as parasite binding to chondroitin sulphate proteoglycan. This is the first study to describe the successful production and functionality of a full-length PfEMP1. The specificity of the binding and anti-adhesion potency of induced IgG, together with high-yield production, encourages the use of full-length PfEMP1 in vaccine development strategies.

Dataset Information

Age-dependent increase in antibodies that inhibit Plasmodium falciparum adhesion to a subset of endothelial receptors.

Publications

Age-dependent increase in antibodies that inhibit Plasmodium falciparum adhesion to a subset of endothelial receptors.

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