A new Python library to analyse skeleton images confirms malaria parasite remodelling of the red blood cell membrane skeleton

Nunez-Iglesias, Juan; Blanch, Adam J.; Looker, Oliver; Dixon, Matthew W. A.; Tilley, Leann

doi:10.7717/peerj.4312

Cited by 68 publications

(42 citation statements)

References 22 publications

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“…e . 49–64 nm [15, 23, 33] and with a study showing that an average of 5 spectrin proteins converge per junctional complex in the RBC membrane skeleton [34]. Given its unusual amino acid composition and predicted disordered domains [10], we also considered the possibility that KAHRP adopts a highly elongated shape.…”

Section: Discussionmentioning

confidence: 99%

The knob protein KAHRP assembles into a ring-shaped structure that underpins virulence complex assembly

et al. 2019

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Plasmodium falciparum mediates adhesion of infected red blood cells (RBCs) to blood vessel walls by assembling a multi-protein complex at the RBC surface. This virulence-mediating structure, called the knob, acts as a scaffold for the presentation of the major virulence antigen, P . falciparum Erythrocyte Membrane Protein-1 (PfEMP1). In this work we developed correlative STochastic Optical Reconstruction Microscopy–Scanning Electron Microscopy (STORM-SEM) to spatially and temporally map the delivery of the knob-associated histidine-rich protein (KAHRP) and PfEMP1 to the RBC membrane skeleton. We show that KAHRP is delivered as individual modules that assemble in situ , giving a ring-shaped fluorescence profile around a dimpled disk that can be visualized by SEM. Electron tomography of negatively-stained membranes reveals a previously observed spiral scaffold underpinning the assembled knobs. Truncation of the C-terminal region of KAHRP leads to loss of the ring structures, disruption of the raised disks and aberrant formation of the spiral scaffold, pointing to a critical role for KAHRP in assembling the physical knob structure. We show that host cell actin remodeling plays an important role in assembly of the virulence complex, with cytochalasin D blocking knob assembly. Additionally, PfEMP1 appears to be delivered to the RBC membrane, then inserted laterally into knob structures.

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Section: Discussionmentioning

confidence: 99%

The knob protein KAHRP assembles into a ring-shaped structure that underpins virulence complex assembly

et al. 2019

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“…It was reported that hepatocyte actin accumulates around the PVM and important actin reorganization events take place during parasite growth 57 . A recent work demonstrated that this is the case also in erythrocytes infected by P. falciparum 58 . Our results support these reports.…”

Section: Discussionmentioning

confidence: 85%

Characterization of the erythrocyte GTPase Rac1 in relation to Plasmodium falciparum invasion

Paone

D’Alessandro

Parapini

et al. 2020

Sci Rep

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Malaria is still a devastating disease with 228 million cases globally and 405,000 lethal outcomes in 2018, mainly in children under five years of age. The threat of emerging malaria strains resistant to currently available drugs has made the search for novel drug targets compelling. The process by which Plasmodium falciparum parasites invade the host cell has been widely studied, but only a few erythrocyte proteins involved in this process have been identified so far. The erythrocyte protein Rac1 is a GTPase that plays an important role in host cell invasion by many intracellular pathogens. Here we show that Rac1 is recruited in proximity to the site of parasite entry during P. falciparum invasion process and that subsequently localizes to the parasitophorous vacuole membrane. We also suggest that this GTPase may be involved in erythrocyte invasion by P. falciparum, by testing the effect of specific Rac1 inhibitory compounds. Finally, we suggest a secondary role of the erythrocyte GTPase also in parasite intracellular development. We here characterize a new erythrocyte protein potentially involved in P. falciparum invasion of the host cell and propose the human GTPase Rac1 as a novel and promising antimalarial drug target.

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“…Proteins associated with junctional complexes such as adducin and tropomyosin also are lost from the cytoskeleton, indicating that some remodeling or dismantling occurs. This is accompanied by an increased spectrin mesh size and the temporal appearance of holes in the cytoskeleton (135,136). This might be the gradual process of dissolving the iRBC cytoskeleton described previously (112), but it is unclear why egress would start so early, since the structural integrity must still be maintained until the merozoites are fully developed.…”

Section: Schizont Stagementioning

confidence: 89%

Host Cytoskeleton Remodeling throughout the Blood Stages of Plasmodium falciparum

Warncke

Beck

2019

Microbiol Mol Biol Rev

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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.

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A new Python library to analyse skeleton images confirms malaria parasite remodelling of the red blood cell membrane skeleton

Cited by 68 publications

References 22 publications

The knob protein KAHRP assembles into a ring-shaped structure that underpins virulence complex assembly

The knob protein KAHRP assembles into a ring-shaped structure that underpins virulence complex assembly

Characterization of the erythrocyte GTPase Rac1 in relation to Plasmodium falciparum invasion

Host Cytoskeleton Remodeling throughout the Blood Stages of Plasmodium falciparum

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