Impaired cytoadherence of Plasmodium falciparum -infected erythrocytes containing sickle hemoglobin

Abstract

Sickle trait, the heterozygous state of normal hemoglobin A (HbA) and sickle hemoglobin S (HbS), confers protection against malaria in Africa. AS children infected with Plasmodium falciparum are less likely than AA children to suffer the symptoms or severe manifestations of malaria, and they often carry lower parasite densities than AA children. The mechanisms by which sickle trait might confer such malaria protection remain unclear. We have compared the cytoadherence properties of parasitized AS and AA erythrocytes, because it is by these properties that parasitized erythrocytes can sequester in postcapillary microvessels of critical tissues such as the brain and cause the life-threatening complications of malaria. Our results show that the binding of parasitized AS erythrocytes to microvascular endothelial cells and blood monocytes is significantly reduced relative to the binding of parasitized AA erythrocytes. Reduced binding correlates with the altered display of P. falciparum erythrocyte membrane protein-1 (PfEMP-1), the parasite's major cytoadherence ligand and virulence factor on the erythrocyte surface. These findings identify a mechanism of protection for HbS that has features in common with that of hemoglobin C (HbC). Coinherited hemoglobin polymorphisms and naturally acquired antibodies to PfEMP-1 may influence the degree of malaria protection in AS children by further weakening cytoadherence interactions.disease severity ͉ malaria ͉ PfEMP-1 ͉ hemoglobin S ͉ hemoglobin C

Les relations complexes entre hémoglobinopathies et paludisme

“…Quels peuvent être les mécanismes cellulaires en cause ? Ceux en cause dans la protection de l'hôte ont fait l'objet d'études multiples [7] : ils ont majoritairement ciblé l'HbS, dont l'impact en santé est majeur en Afrique, mettant en évidence chez les hétérozygotes AS plusieurs mécanismes de protection : diminution de l'invasion parasitaire des GR, moindre formation de rosettes et modification de l'adhérence des érythro-cytes AS infectés à l'endothélium [10]. Concernant l'HbC, on a montré une moindre expression de l'antigène PfEMP-1 du parasite modifiant l'adhérence à la paroi vasculaire de globules rouges porteurs de cette hémoglobine [11].…”

An evolving picture of the interactions between malaria parasites and their host erythrocytes

“…Cryklaff et al [1] report that P. falciparum remodels host actin into a network of filaments associated with Maurer's clefts and the erythrocyte membrane; this network may support protein and vesicle trafficking to the knobs. Hemoglobin variants HbS and HbC interfere with proper knob formation and PfEMP1 display, weaken the binding of parasitized erythrocytes to endothelium and may thereby reduce sequestration-related pathology [5,8]. Aberrant Maurer's clefts and compromised remodeling of the actin network occur in HbSC and HbCC erythrocytes [1]; these abnormalities remain to be demonstrated in HbAS and HbAC erythrocytes.…”

“…Although early studies implicated poor growth of P. falciparum in HbAS erythrocytes as a mechanism of protection that keeps parasitemias low, other work found that laboratory-adapted parasite clones grew normally in HbAS erythrocytes even under reduced oxygen conditions [4,5]. Further, it was clear that substantial parasitemias and frequent episodes of uncomplicated malaria occurred in HbAS as well as HbAA children, despite marked differences in the incidence of severe malaria between these groups [6].…”

“…These field observations suggest a mechanism of protection that, instead of merely reducing the numbers of parasitized erythrocytes in the circulation, works to ameliorate the inflammation that arises at the host-parasite interface from the interactions of infected erythrocytes with the endothelium and other blood elements. Indeed, parasitized HbAC and HbAS erythrocytes show significant impairment of cytoadherence in association with perturbed display of the P. falciparum major cytoadherence npg protein (PfEMP1) on abnormal knob protrusions [5,8].…”

Evidence for epistasis between hemoglobin C and immune genes in human P. falciparum malaria: a family study in Burkina Faso

“…The abnormal display of PfEMP-1 on AC and CC red blood cells also lead to a reduced CD36 phagocytosis of trophozoite-infected cells by blood monocytes, suggesting that HbC does not protect against malaria by enhancing phagocytosis. 15 However, HbC carriers have been found to produce increased levels of immunoglobulin-G directed against several plasmodial antigens, 16,17 suggesting that HbC may increase antibodydependent phagocytosis or cytotoxicity, may accelerate naturally acquired immunity, and may interact with genes involved in immune responses. Besides, natural killer (NK) cells have been found to recognize PfEMP-1 at the surface of infected red blood cells via NKp30, 18 suggesting that the abnormal display of PfEMP-1 on AC and CC red blood cells may alter the activation of NK cells.…”