Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria

Abstract

Haemoglobin C, which carries a glutamate-to-lysine mutation in the beta-globin chain, protects West African children against Plasmodium falciparum malaria. Mechanisms of protection are not established for the heterozygous (haemoglobin AC) or homozygous (haemoglobin CC) states. Here we report a marked effect of haemoglobin C on the cell-surface properties of P. falciparum-infected erythrocytes involved in pathogenesis. Relative to parasite-infected normal erythrocytes (haemoglobin AA), parasitized AC and CC erythrocytes show reduced adhesion to endothelial monolayers expressing CD36 and intercellular adhesion molecule-1 (ICAM-1). They also show impaired rosetting interactions with non-parasitized erythrocytes, and reduced agglutination in the presence of pooled sera from malaria-immune adults. Abnormal cell-surface display of the main variable cytoadherence ligand, PfEMP-1 (P. falciparum erythrocyte membrane protein-1), correlates with these findings. The abnormalities in PfEMP-1 display are associated with markers of erythrocyte senescence, and are greater in CC than in AC erythrocytes. Haemoglobin C might protect against malaria by reducing PfEMP-1-mediated adherence of parasitized erythrocytes, thereby mitigating the effects of their sequestration in the microvasculature.

Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting

“…A polymorphism resulting in erythrocyte complement receptor (CR) 1 deficiency that is found at high frequency in Melanesian populations exposed to malaria is associated with reduced P. falciparum rosetting (spontaneous binding of infected erythrocytes to uninfected erythrocytes) (3) and protection against severe disease (4). The protective effects of thalassemia, sickle cell trait, and HbC may also be partly caused by reduced rosetting (5,6). Rosetting is a known parasite virulence factor (7,8) that is thought to contribute to the pathogenesis of severe malaria by obstructing microvascular blood flow (9).…”

Les relations complexes entre hémoglobinopathies et paludisme

“…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]. Ces mécanismes concernent tous les formes parasitaires asexuées, mais en revanche, on sait peu de choses sur la façon dont le génotype HBB pourrait influencer la formation des gamétocytes en fin de cycle asexué chez l'hôte.…”

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

“…This is further supported by evidence of a positive selection, 9,10 and by in vitro studies with human cells. [11][12][13][14] Although the molecular mechanisms behind the protection remain to be elucidated, several mechanisms have been proposed: (i) a low capacity of the parasite to replicate in red blood cells; (ii) an altered expression of parasite antigens on the surface of red blood cells leading to a diminished cytoadhesion and/or an altered immune response; (iii) and an increased phagocytosis of the infected red blood cells. Several studies have demonstrated in vitro that the growth of the parasite was inhibited in CC cells, [12][13][14] whereas the parasite grows normally in AC cells.…”