A spiral scaffold underlies cytoadherent knobs in Plasmodium falciparum-infected erythrocytes

Journal article

Much of the virulence of Plasmodium falciparum malaria is caused by cytoadherence of infected erythrocytes, which promotes parasite survival by preventing clearance in the spleen. Adherence is mediated by membrane protrusions known as knobs, whose formation depends on the parasite-derived, knob-associated histidine-rich protein (KAHRP). Knobs are required for cytoadherence under flow conditions, and they contain both KAHRP and the parasite-derived erythrocyte membrane protein PfEMP1. Using electron tomography, we have examined the three-dimensional structure of knobs in detergent-insoluble skeletons of P. falciparum 3D7 schizonts. We describe a highly organised knob skeleton composed of a spiral structure coated by an electron dense layer underlying the knob membrane. This knob skeleton is connected by multiple links to the erythrocyte cytoskeleton. We used immuno-electron microscopy to locate KAHRP in these structures. The arrangement of membrane proteins in the knobs, visualised by high resolution freeze fracture scanning electron microscopy, is distinct from that in the surrounding erythrocyte membrane, with a structure at the apex that likely represents the adhesion site. Thus, erythrocyte knobs in P. falciparum infection contain a highly organised skeleton structure underlying a specialised region of membrane. We propose that the spiral and dense coat organise the cytoadherence structures in the knob, and anchor them into the erythrocyte cytoskeleton. The high density of knobs and their extensive mechanical linkage suggest an explanation for the rigidification of the cytoskeleton in infected cells, and for the transmission to the cytoskeleton of shear forces experienced by adhering cells.

Authors: Watermeyer, J; Hale, V; Hackett, F; Clare, D; Cutts, E

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society of Hematology
• Journal: Blood
• Volume: 127
• Issue: 3
• Pages: 343-351
• Publication date: 2016-01-21
• Acceptance date: 2015-11-30
• DOI: 10.1182/blood-2015-10-674002
• EISSN: 1528-0020
• ISSN: 0006-4971