Early gametocytes of the malaria parasitePlasmodium falciparumspecifically remodel the adhesive properties of infected erythrocyte surface

Abstract

SummaryIn Plasmodium falciparum infections the parasite transmission stages, the gametocytes, mature in 10 days sequestered in internal organs. Recent studies suggest that cell mechanical properties rather than adhesive interactions play a role in sequestration during gametocyte maturation. It remains instead obscure how sequestration is established, and how the earliest sexual stages, morphologically similar to asexual trophozoites, modify the infected erythrocytes and their cytoadhesive properties at the onset of gametocytogenesis. Here, purified P. falciparum early gametocytes were used to ultrastructurally and biochemically analyse parasite-induced modifications on the red blood cell surface and to measure their functional consequences on adhesion to human endothelial cells. This work revealed that stage I gametocytes are able to deform the infected erythrocytes like asexual parasites, but do not modify its surface with adhesive 'knob' structures and associated proteins. Reduced levels of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesins are exposed on the red blood cell surface by these parasites, and the expression of the var gene family, which encodes 50-60 variants of PfEMP1, is dramatically downregulated in the transition from asexual development to gametocytogenesis. Cytoadhesion assays show that such gene expression changes and host cell surface modifications functionally result in the inability of stage I gametocytes to bind the host ligands used by the asexual parasite to bind endothelial cells. In conclusion, these results identify specific differences in molecular and cellular mechanisms of host cell remodelling and in adhesive properties, leading to clearly distinct host parasite interplays in the establishment of sequestration of stage I gametocytes and of asexual trophozoites.

Molecular evidence for the localization of Plasmodium falciparum immature gametocytes in bone marrow

“…The very low transcript levels of immature gametocytes in the peripheral blood of 20% of the children suggest that the highly sensitive qPCR might be detecting residual early sexual stages in the bloodstream that may have escaped from the bone marrow. These results are in agreement with recent findings suggesting that mechanical properties of erythrocytes infected by immature gametocyte stages (ie, decreased deformability leading to the retention of immature gametocytes within the marrow) [37][38][39] may play a role in their localization in the bone marrow. However, it cannot be ruled out that cytoadhesion of erythrocytes infected by sexually committed trophozoites to specific receptors in the bone marrow may contribute to the enrichment of early sexual stages in this organ.…”

Biology of Malaria Transmission

“…1C) (Nilsson et al 2015;Pelle et al 2015). In contrast to asexual stages, early gametocytes do not significantly modify the RBC, as minimal levels of PfEMP-1 are expressed on the infected RBC surface and no significant knob structures were observed Tiburcio et al 2013). This difference in surface protein expression is consistent with in vitro studies in which immature gametocytes showed significantly less, if any, binding to purified host ligands (CD36, ICAM-1) (Day et al 1998) and to bone marrow endothelium or other endothelial cell lines .…”

Plasmodium falciparum STEVOR phosphorylation regulates host erythrocyte deformability enabling malaria parasite transmission

“…10,11,45,46 The rise in the knob density in mature asexual stages results in the increased number of vertical constraints between the spectrin network and the lipid bilayer, which further stiffens the membrane. 47 In GIEs, KAHRP and PfEMP1 are not expressed 48,49 and STEVORs may perform an analogous role by increasing vertical constraints between the cytoskeleton and the lipid bilayer. Protein-protein interactions essential for the erythrocyte membrane mechanical properties are modulated by posttranscriptional modifications of either cytoskeleton or parasite proteins.…”