Abstract
SummaryAdherence of Plasmodium falciparum‐infected erythrocytes to host endothelium is conferred through the parasite‐derived virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1), the major contributor to malaria severity. PfEMP1 located at knob structures on the erythrocyte surface is anchored to the cytoskeleton, and the Plasmodium helical interspersed subtelomeric (PHIST) gene family plays a role in many host cell modifications including binding the intracellular domain of PfEMP1. Here, we show that conditional reduction of the PHIST protein PFE1605w strongly reduces adhesion of infected erythrocytes to the endothelial receptor CD36. Adhesion to other endothelial receptors was less affected or even unaltered by PFE1605w depletion, suggesting that PHIST proteins might be optimized for subsets of PfEMP1 variants. PFE1605w does not play a role in PfEMP1 transport, but it directly interacts with both the intracellular segment of PfEMP1 and with cytoskeletal components. This is the first report of a PHIST protein interacting with key molecules of the cytoadherence complex and the host cytoskeleton, and this functional role seems to play an essential role in the pathology of P. falciparum.
Highlights
After invading the human erythrocyte, the malaria parasite Plasmodium falciparum refurbishes its host cell dramatically
Adherence of Plasmodium falciparum-infected erythrocytes to host endothelium is conferred through the parasite-derived virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1), the major contributor to malaria severity
PfEMP1 located at knob structures on the erythrocyte surface is anchored to the cytoskeleton, and the Plasmodium helical interspersed subtelomeric (PHIST) gene family plays a role in many host cell modifications including binding the intracellular domain of PfEMP1
Summary
After invading the human erythrocyte, the malaria parasite Plasmodium falciparum refurbishes its host cell dramatically. The most important changes lead to sequestration of infected cells to the microvasculature of human organs – the sole cause of morbidity and mortality in malaria tropica. These changes allow the malaria parasite to grow in a parasitophorous vacuole inside the erythrocyte and enable nutrient uptake. It is difficult to predict the true number of PEXEL-negative exported proteins and the total number of exported proteins (Heiber et al, 2013) The export of both groups of proteins results in profound structural and morphological changes in the erythrocyte. For example it causes the formation of electron-dense protrusions on the erythrocyte surface, called knobs (Watermeyer et al, 2016), alters red blood cell (RBC) rigidity (Maier et al, 2008) and increases membrane permeability (Nguitragool et al, 2011)
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