Host Cytoskeleton Remodeling throughout the Blood Stages of Plasmodium falciparum

Abstract

The asexual intraerythrocytic development of Plasmodium falciparum, causing the most severe form of human malaria, is marked by extensive host cell remodeling. Throughout the processes of invasion, intracellular development, and egress, the erythrocyte membrane skeleton is remodeled by the parasite as required for each specific developmental stage. The remodeling is facilitated by a plethora of exported parasite proteins, and the erythrocyte membrane skeleton is the interface of most of the observed interactions between the parasite and host cell proteins. Host cell remodeling has been extensively described and there is a vast body of information on protein export or the description of parasite-induced structures such as Maurer's clefts or knobs on the host cell surface. Here we specifically review the molecular level of each host cell-remodeling step at each stage of the intraerythrocytic development of P. falciparum We describe key events, such as invasion, knob formation, and egress, and identify the interactions between exported parasite proteins and the host cell cytoskeleton. We discuss each remodeling step with respect to time and specific requirement of the developing parasite to explain host cell remodeling in a stage-specific manner. Thus, we highlight the interaction with the host membrane skeleton as a key event in parasite survival.

Keywords: cytoskeleton; erythrocytes; gametocytes; malaria; remodeling.

FIG 1

Overview of the intraerythrocytic cycle of P. falciparum. A summary of some of the parasite-mediated changes occurring at the erythrocyte cytoskeleton throughout the asexual blood stages is shown. The first box shows the spectrin-actin network connected to the RBC membrane vertically linked to proteins such as band 3 in the uninfected RCB (uRBC). During invasion, the RBC cytoskeleton is locally rearranged by kinase and protease activity (box 2). During the ring stage, first exported parasite proteins target the iRBC cytoskeleton, and parasite-induced structures such as Maurer’s clefts are found (box 3). The maturing parasite forms knobs, surface protrusions which anchor PfEMP1 (box 4), and merozoites are formed during the last hours of the intraerythrocytic life cycle (box 5). During egress, the PVM is permeabilized, and the iRBC cytoskeleton and membrane are degraded to release the newly formed merozoites into the bloodstream (box 6).

FIG 2

Invasion. Individual steps of invasion are shown, focusing on changes to the erythrocyte cytoskeleton. The initial contact between merozoite and erythrocyte is mediated by binding of MSP1 to its RBC receptor (box 1), which then causes a reorientation of the merozoite. An increase in intracellular calcium leads to local reorganization of the erythrocyte cytoskeleton (boxes 2 and 3). Once the parasite has reoriented its apical end facing the RBC membrane, stronger binding by EBL and Rh5 complex proteins occurs (box 4). A tight junction is formed, and proteases locally degrade the cytoskeleton to create an opening for the inward-pushing parasite (boxes 5 and 6).

FIG 3

Hypothetical changes during the transition phase. This figure summarizes and chronologically orders the events occurring during the transition from the ring stage to the trophozoite stage. RESA disappears from the cytoskeleton, and actin mining starts (box 1). Knobs are formed, PfEMP1 is found on the surface, and MESA targets the cytoskeleton. Spectrin ends are connected to knobs, and growing actin filaments connect Maurer’s clefts to the iRBC cytoskeleton (boxes 2 and 3). MCs are now arrested and in closer proximity to the iRBC membrane (box 4). The figure in part was inspired by reference and additional information from references and .

FIG 4

Cytoskeleton time course in asexual stages. (Upper panel) Changes in phosphorylation level and cellular rigidity over the course of the intraerythrocytic asexual development of P. falciparum (approximations). (Lower panel) Changes occurring in the spectrin network over the course of development, as described in references , , and .

FIG 5

Overview of the events occurring during merozoite egress About 10 to 30 min before egress, the PVM is permeabilized (box 1). Triggered by PfPKG, the parasite protease SUB1 is activated and discharged from exonemes. SUB1 then cleaves and activates SERA6 and the merozoite surface protein MSP1 (box 2). The permeabilized PVM eventually forms multilamellar vesicles. SERA6 and SUB1 degrade cytoskeletal proteins (box 3). Other parasite proteases previously found in the food vacuole (box 4) as well as matured MSP1 also assist in cytoskeleton breakdown (box 5). The pore-forming protein PfPLP1 is secreted from the micronemes and lyses the iRBC membrane, which eventually curls (box 6). The arrows indicate movement of proteases as well as their substrate-processing activity.

FIG 6

Cytoskeleton time course during gametocyte development. (A) Upper panel, changes in phosphorylation level and cellular rigidity over the course of gametocyte development (approximations). Lower panel, changes occurring in the spectrin network over the course of development, as described in reference . (B) Giemsa-stained stage III P. falciparum gametocytes (image courtesy of A. Passecker). (C) Giemsa-stained macro- and microgametocytes of several human Plasmodium species, showing the unique morphology of sequestering P. falciparum gametocytes (image courtesy of Y. Endriss).