Abstract
Cholesterol, a necessary component of animal cell membranes, is also needed by the lethal human malaria parasite Plasmodium falciparum. Because P. falciparum lacks a cholesterol synthesis pathway and malaria patients have low blood cholesterol, we speculated that it scavenges cholesterol from them in some way. We used time-lapse holotomographic microscopy to observe cholesterol transport in live P. falciparum parasites and structurally investigate erythrocyte membranes, both during and after P. falciparum invasion of human erythrocytes. After P. falciparum initially acquired free cholesterol or inner erythrocytic membrane-derived cholesterol, we observed budding lipid membranes elongating into the cytosol and/or membrane segments migrating there and eventually fusing with the parasite membranes, presumably at the parasitophorous vacuole membrane (PVM). Finally, the cholesterol-containing segments were seen to surround the parasite nucleus. Our imaging data suggest that a novel membrane transport system operates in the cytosol of P. falciparum-infected erythrocytes as a cholesterol import system, likely between the PVM and the erythrocyte membrane, and that this transportation process occurs during the live erythrocyte stages of P. falciparum.
Highlights
Malaria, an infectious disease caused by Plasmodium species, still retains its prevalence in tropical and subtropical regions of the world, in Africa and East South Asia
To confirm that the observed elongated membranes and/or vesicle membranes are associated with live intraerythrocytic P. falciparum parasites, we examined the effects of DHA48,49 on a non-synchronized P. falciparum culture
The role of the tubovesicular network (TVN), which secretes buds from the parasitophorous vacuole membrane (PVM), is to transport sphingomyelin and proteins, including the raft fraction, to the erythrocyte membrane via its elongation[54,55]. This is accompanied by an increased surface area of the TVN, and occurs at the PVM, which becomes larger as the parasite grows
Summary
An infectious disease caused by Plasmodium species (spp.), still retains its prevalence in tropical and subtropical regions of the world, in Africa and East South Asia. Our tomographic images show four different RI depictions of an individual nRBC, where the areas with specific RI values were found to range from 1.331–1.353 for the outer leaflet (colored red), 1.330–1.403 for the inner leaflet (colored yellow), and 1.369–1.397 for the cytoskeleton or the protein complex (colored blue), while the remaining gray colored area is the cytosol (Fig. 1H) These results correspond with the known structural aspects of nRBC partitioning of the cytosol, membrane cytoskeleton, inner leaflet, and outer leaflet[40]. The outer membrane (shown in red) and membrane cytoskeleton/membrane protein complex (shown in blue) were irregularly shaped in the nRBCs treated with 10 μM MβCD (Fig. 1L) These data confirm that holotomographic imaging can successfully reveal the multiple layers of the erythrocyte membrane. The changes to the inner leaflet (shown in yellow) in response to MβCD treatment are suggestive of the presence of cholesterol in the inner leaflet, and the structural aspects of the erythrocyte involving RI mapping were stable (Supplemental Movie 1) without MβCD
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