The mechanics of malaria parasite invasion of the human erythrocyte – towards a reassessment of the host cell contribution

Koch, Marion; Baum, Jake

doi:10.1111/cmi.12557

Cited by 59 publications

(56 citation statements)

References 86 publications

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“…This finding contradicted our expectation that increased cross-linking of the GPA tail upon EBA175 binding might be functional for invasion, for instance, serving as a focal point where the RBC cytoskeleton could be opened up around the invading parasite or providing stability for the tight junction (46). This result suggests that direct cross-linking of GPA to the cytoskeleton via its cytoplasmic tail does not significantly impact invasion efficiency.…”

Section: Discussioncontrasting

confidence: 77%

Plasmodium falciparum erythrocyte-binding antigen 175 triggers a biophysical change in the red blood cell that facilitates invasion

Koch

Wright

Otto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Invasion of the red blood cell (RBC) by the Plasmodium parasite defines the start of malaria disease pathogenesis. To date, experimental investigations into invasion have focused predominantly on the role of parasite adhesins or signaling pathways and the identity of binding receptors on the red cell surface. A potential role for signaling pathways within the erythrocyte, which might alter red cell biophysical properties to facilitate invasion, has largely been ignored. The parasite erythrocyte-binding antigen 175 (EBA175), a protein required for entry in most parasite strains, plays a key role by binding to glycophorin A (GPA) on the red cell surface, although the function of this binding interaction is unknown. Here, using real-time deformability cytometry and flicker spectroscopy to define biophysical properties of the erythrocyte, we show that EBA175 binding to GPA leads to an increase in the cytoskeletal tension of the red cell and a reduction in the bending modulus of the cell's membrane. We isolate the changes in the cytoskeleton and membrane and show that reduction in the bending modulus is directly correlated with parasite invasion efficiency. These data strongly imply that the malaria parasite primes the erythrocyte surface through its binding antigens, altering the biophysical nature of the target cell and thus reducing a critical energy barrier to invasion. This finding would constitute a major change in our concept of malaria parasite invasion, suggesting it is, in fact, a balance between parasite and host cell physical forces working together to facilitate entry.erythrocyte | malaria | real-time deformability cytometry | flicker spectroscopy | merozoite M alaria infections cause ∼438,000 deaths per year, most of which are due to the protozoan parasite Plasmodium falciparum (1). Although extensive eradication efforts have helped to reduce the incidence of malaria, the spread of drug resistance is a growing concern and novel treatments are urgently needed (2). Throughout the Plasmodium life cycle, parasites shuttle between replicative and motile life-cycle stages, with the motile forms or "zoites" highly adapted to the invasion of host cells. During the blood stages of infection, the merozoite targets and invades the red blood cell (RBC) rapidly (< 30 s) in a process that involves numerous parasite ligands and host cell receptors (3). Merozoite entry is a multistep process commencing with initial attachment and ending with parasite actomyosin-driven invasion (4). Although extensive cellular and molecular details of each step have been elucidated (5, 6), there is still little mechanistic understanding of the role of each protein involved or the signaling events within the erythrocyte that accompany entry (7).Initial attachment to the RBC surface is likely mediated by merozoite surface proteins. Subsequently, the key signaling and strong attachment interactions between host and parasite membranes are thought to be mediated by two major classes of adhesins released either before or concomitant with inva...

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Section: Discussioncontrasting

confidence: 77%

Plasmodium falciparum erythrocyte-binding antigen 175 triggers a biophysical change in the red blood cell that facilitates invasion

Koch

Wright

Otto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The clinically symptomatic asexual cycle of replication of Plasmodium in red blood cells begins with a loose association of the merozoite with the erythrocyte surface, followed by reorientation to establish apical contact with the cell, followed by irreversible attachment of the merozoite and creation of a tight junction that allows the progressive entrance into the cell, and ultimately the establishment of the parasitophorous vacuole; each one of these steps requiring multiple protein-protein interactions of the parasite with the erythrocyte (reviewed in Cowman et al, 2012; Koch and Baum, 2016). Once the merozoite has sealed itself inside the erythrocyte, protein export and remodeling of the cell begins.…”

Section: 6-cys Proteins In Asexual Erythrocytic Stagesmentioning

confidence: 99%

The s48/45 six-cysteine proteins: mediators of interaction throughout the Plasmodium life cycle

Arredondo

Kappe

2017

International Journal for Parasitology

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During their life cycle Plasmodium parasites rely upon an arsenal of proteins that establish key interactions with the host or vector, and between the parasite sexual stages, with the purpose of ensuring infection, reproduction and proliferation. Among these is a group of secreted or membrane-anchored proteins known as the six-cysteine (6-cys) family. This is a small but important family with only 14 members thus far identified, each stage-specifically expressed during the parasite life cycle. 6-cys proteins often localize at the parasite surface or interface with the host and are conserved in different Plasmodium species. The unifying feature of the family is the s48/45 domain, presumably involved in adhesion and structurally related to Ephrins, the ligands of Eph receptors. The most prominent s48/45 members are currently under functional investigation and are being pursued as vaccine candidates. In this review, we examine what is known about the 6-cys family, their structure and function, and discuss future research directions.

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“…RBC invasion by merozoites is preceded by three key events: (i) initial attachment, (ii) re-orientation or alignment of the parasite such that its apex is facing the RBC membrane, and (iii) formation of a tight junction [7]. The apex contains all required machinery to invade RBCs after the tight junction is formed [8].…”

Section: Introductionmentioning

confidence: 99%

Stochastic bond dynamics facilitates alignment of malaria parasite at erythrocyte membrane upon invasion

Hillringhaus

Dasanna

Gompper

et al. 2020

Preprint

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Malaria parasites invade healthy red blood cells (RBCs) during the blood stage of the disease. Even though parasites initially adhere to RBCs with a random orientation, they need to align their apex toward the membrane in order to start the invasion process. Using hydrodynamic simulations of a RBC and parasite, where both interact through discrete stochastic bonds, we show that parasite alignment is governed by the combination of RBC membrane deformability and dynamics of adhesion bonds. The stochastic nature of bond-based interactions facilitates a diffusive-like re-orientation of the parasite at the RBC membrane, while RBC deformation aids in the establishment of apexmembrane contact through partial parasite wrapping by the membrane. This bond-based model for parasite adhesion quantitatively captures alignment times measured experimentally and demonstrates that alignment times increase drastically with increasing rigidity of the RBC membrane. Our results suggest that the alignment process is mediated simply by passive parasite adhesion.

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The mechanics of malaria parasite invasion of the human erythrocyte – towards a reassessment of the host cell contribution

Cited by 59 publications

References 86 publications

Plasmodium falciparum erythrocyte-binding antigen 175 triggers a biophysical change in the red blood cell that facilitates invasion

Plasmodium falciparum erythrocyte-binding antigen 175 triggers a biophysical change in the red blood cell that facilitates invasion

The s48/45 six-cysteine proteins: mediators of interaction throughout the Plasmodium life cycle

Stochastic bond dynamics facilitates alignment of malaria parasite at erythrocyte membrane upon invasion

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