Electron tomography ofPlasmodium falciparummerozoites reveals core cellular events that underpin erythrocyte invasion

• DOI: 10.1111/cmi.12132
• Publication Date: 2013-03-05T15:34:35Z
• Authors: Eric Hanssen; Chaitali Dekiwadia; David T. Riglar; Melanie Rug; Leandro Lemgruber; Alan F. Cowman; Marek Cyrklaff; Mikhail Kudryashev; Friedrich Frischk...; Jake Baum; Stuart A. Ralph
• Keywords: 0301 basic medicine; 570; Electron Microscope Tomography; Erythrocytes; Plasmodium falciparum; cell organelle; cryoelectron microscopy; electron tomography; malaria falciparum; computer assisted tomography; Keywords: article; 03 medical and health sciences; cell nucleus membrane; Imaging, Three-Dimensional; intracellular space; 616; Humans; nonhuman; electron microscopy; Merozoites; merozoite; Endocytosis; 3. Good health; Host-Pathogen Interactions; erythrocyte; microtubule

Erythrocyte invasion by merozoites forms of the malaria parasite is a key step in the establishment of human malaria disease. To date, efforts to understand cellular events underpinning entry have been limited to insights from non-human parasites, with no studies at sub-micrometer resolution undertaken using the most virulent human malaria parasite, Plasmodium falciparum. This leaves our understanding of the dynamics of merozoite sub-cellular compartments during infectionincomplete, in particular that of the secretory organelles. Using advances in P. falciparum merozoite isolation and new imaging techniques we present a three-dimensional study of invasion using electron microscopy, cryo-electron tomography and cryo-X-ray tomography. We describe the core architectural features of invasion and identify fusion between rhoptries at the commencement of invasion as a hitherto overlooked event that likely provides a critical step that initiates entry. Given the centrality of merozoite organelle proteins to vaccine development, these insights provide a mechanistic framework to understand therapeutic strategies targeted towards the cellular events of invasion.