Host Cytoskeleton Remodeling throughout the Blood Stages of Plasmodium falciparum

Abstract

SUMMARYThe asexual intraerythrocytic development ofPlasmodium 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 ofP. 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.

KAHRP dynamically relocalizes to remodeled actin junctions and associates with knob spirals in P. falciparum-infected erythrocytes

“…PfEMP1, the spectrin filaments (via a quaternary complex consisting of the N-terminus of ßspectrin and protein 4.1R), and the long actin filaments. A "glue-like" function would be consistent with the multi-modular binding properties of KAHRP (Warncke and Beck, 2019).…”

“…These protrusions, termed knobs, play a pivotal role in the pathophysiology of falciparum malaria. They form a platform on which parasite-encoded adhesins, such as the immune-variant PfEMP1 antigens, are presented and anchored to the membrane skeleton (Warncke and Beck, 2019). As a result, parasitized erythrocytes attain cytoadhesive properties and sequester in the deep vascular bed of inner organs, which, in turn, can lead to severe sequelae including impaired tissue perfusion, hypoxia and local microvascular inflammation followed by barrier dysfunction (Lee et al, 2019;Smith et al, 2013).…”

Implicating extracellular vesicles in Plasmodium falciparum artemisinin resistance development

“…First is the parasite membrane, then the parasitophorous vacuole membrane (PVM), and finally the red blood cell (RBC) membrane 25 . However, it is an established fact that extensive host Pf iRBC remodeling achieves active transportation of parasite antigens across all membranes and supports the hypothesis that EVs from Pf iRBCs may play a role in mediating P‐PC in P. falciparum 26 …”

Host autophagy is a shared target of virulence factors of Phytophthora infestans and Plasmodium parasite

“…To ensure rapid reproduction, Plasmodium must evade surveillance by the host immune system while acquiring nutrients from the host. To achieve this goal, Plasmodium secretes effector proteins to the host cytoskeleton and plasma membrane; these proteins alter cell adhesion, deformability and permeability, prevent immune clearance, and provide the nutrients needed to support Plasmodium survival and reproduction in its ecological niche (Table 1) (de Koning‐Ward et al., 2016; Matthews et al., 2019; Spillman et al., 2015; Ukegbu et al., 2020; Warncke & Beck, 2019). In addition, the effector proteins facilitate the efficient delivery of exported proteins to specific subcellular sites in the host (Table 1) (McHugh et al, 2020).…”

“…In addition to avoiding immune clearance, Plasmodium also modifies the permeability of the host cell membrane through secreted virulence factors; this modification allows the absorption of nutrients such as sugar and amino acids to meet the rapid growth of the parasite and to produce more merozoites (Matthews et al., 2019). Moreover, toxic metabolites produced by Plasmodium can be deposed in time (Warncke & Beck, 2019). RhopH protein family members play an important role in remodelling host cell permeability (Counihan et al., 2017; Ito et al., 2017; Sherling et al., 2017).…”