Knobs, Adhesion, and Severe Falciparum Malaria

Abstract

Plasmodium falciparum can cause a severe disease with high mortality. A major factor contributing to the increased virulence of P. falciparum, as compared to other human malarial parasites, is the sequestration of infected erythrocytes in the capillary beds of organs and tissues. This sequestration is due to the cytoadherence of infected erythrocytes to endothelial cells. Cytoadherence is primarily mediated by a parasite protein expressed on the surface of the infected erythrocyte called P. falciparum erythrocyte membrane protein-1 (PfEMP1). PfEMP1 is embedded in electron-dense protuberances on the surface of the infected erythrocytes called knobs. These knobs are assembled on the erythrocyte membrane via exported parasite proteins, and the knobs function as focal points for the cytoadherence of infected erythrocytes to endothelial cells. PfEMP1 is a member of the var gene family, and there are approximately 60 antigenically distinct PfEMP1 alleles per parasite genome. Var gene expression exhibits allelic exclusion, with only a single allele being expressed by an individual parasite. This results in sequential waves of antigenically distinct infected erythrocytes and this antigenic variation allows the parasite to establish long-term chronic infections. A wide range of endothelial cell receptors can bind to the various PfEMP1 alleles, and thus, antigenic variation also results in a change in the cytoadherence phenotype. The cytoadherence phenotype may result in infected erythrocytes sequestering in different tissues and this difference in sequestration may explain the wide range of possible clinical manifestations associated with severe falciparum malaria.

Comparative analysis of codon usage patterns of Plasmodium helical interspersed subtelomeric (PHIST) proteins

“…Inside the red blood cells, the parasites multiply and eventually cause the cells to rupture, releasing more merozoites to infect other red blood cells. Multiple studies have identified various invasion-related protein molecules mediating the invasion process of Plasmodium falciparum , such as Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), Plasmodium falciparum merozoite surface protein 1 (PfMSP1), Plasmodium falciparum apical membrane antigen 1 (PfAMA1), Plasmodium falciparum rhoptry neck protein 4 (PfRON4), with PfEMP1 being particularly important ( Lee et al, 2023 ; Leonard et al, 2023 ; Pulido-Quevedo et al, 2023 ; Wiser, 2023 ). In recent years, the involvement of Plasmodium helical interspersed subtelomeric (PHIST) proteins in the invasion process has also been investigated.…”