Plasmodium falciparum ligand binding to erythrocytes induce alterations in deformability essential for invasion

The most lethal form of malaria in humans is caused by Plasmodium falciparum. These parasites invade erythrocytes, a complex process involving multiple ligand-receptor interactions. The parasite makes initial contact with the erythrocyte followed by dramatic deformations linked to the function of the Erythrocyte binding antigen family and P. falciparum reticulocyte binding-like families. We show EBA-175 mediates substantial changes in the deformability of erythrocytes by binding to glycophorin A and activating a phosphorylation cascade that includes erythrocyte cytoskeletal proteins resulting in changes in the viscoelastic properties of the host cell. TRPM7 kinase inhibitors FTY720 and waixenicin A block the changes in the deformability of erythrocytes and inhibit merozoite invasion by directly inhibiting the phosphorylation cascade. Therefore, binding of P. falciparum parasites to the erythrocyte directly activate a signaling pathway through a phosphorylation cascade and this alters the viscoelastic properties of the host membrane conditioning it for successful invasion. DOI: http://dx.doi.org/10.7554/eLife.21083.001

• Publication year

  2017

• Venue

  eLife

• Publication date

  2017-01-18

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.7554/eLife.21083PMID 28226242PMCID 5333951
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• FTY720 and waixenicin A block the deformability changes and inhibit merozoite invasion by directly inhibiting the phosphorylation cascade.

  Confidence 0.96

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• EBA-175 mediates substantial changes in erythrocyte deformability.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• EBA-175 binding to glycophorin A is linked to activation of a phosphorylation cascade in erythrocytes that involves cytoskeletal proteins and alters host-cell viscoelastic properties.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review

• eba-175

  protein

  A Plasmodium falciparum erythrocyte binding antigen involved in attachment to red blood cells.

  Aliases: erythrocyte binding antigen 175

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• erythrocyte deformability

  biophysical property

  The mechanical ability of red blood cells to change shape under force, measured here as a host-cell property.

  Aliases: red blood cell deformability

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• glycophorin a

  glycoprotein, receptor

  A major erythrocyte surface glycoprotein that serves as the binding partner for EBA-175 in this work.

  Aliases: GPA

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• merozoite invasion

  parasite process

  The entry process by which malaria merozoites invade erythrocytes.

  Aliases: parasite invasion of erythrocytes

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• phosphorylation cascade

  signaling pathway

  A sequence of phosphorylation events in the erythrocyte that is activated downstream of parasite binding in this paper.

  Aliases: phosphorylation signaling cascade

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review
• trpm7 kinase inhibitors

  inhibitor

  Small-molecule inhibitors used here to interfere with TRPM7-associated kinase activity, including FTY720 and waixenicin A.

  Aliases: FTY720, waixenicin A

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewq (76h6bfydm6) review

• Essential Role of the PfRh5/PfRipr/CyRPA Complex during Plasmodium falciparum Invasion of Erythrocytes.

  2016influential reference
• Multiple Plasmodium falciparum Merozoite Surface Protein 1 Complexes Mediate Merozoite Binding to Human Erythrocytes*

  2016influential reference
• Quantitative phospho-proteomics reveals the Plasmodium merozoite triggers pre-invasion host kinase modification of the red cell cytoskeleton

  2016cited by this paper
• Piezo1 links mechanical forces to red blood cell volume

  2015cited by this paper
• Revealing the Sequence and Resulting Cellular Morphology of Receptor-Ligand Interactions during Plasmodium falciparum Invasion of Erythrocytes

  2015influential reference
• Plasmodium falciparum Adhesins Play an Essential Role in Signalling and Activation of Invasion into Human Erythrocytes

  2015cited by this paper
• Direct Cytoskeleton Forces Cause Membrane Softening in Red Blood Cells.

  2015cited by this paper
• STRUCTURAL AND FUNCTIONAL ANALYSIS

  2015influential reference
• Intrinsic disorder within the erythrocyte binding-like proteins from Plasmodium falciparum.

  2014influential reference
• Critical Glycosylated Residues in Exon Three of Erythrocyte Glycophorin A Engage Plasmodium falciparum EBA-175 and Define Receptor Specificity

  2014cited by this paper
• A Kinase Inhibitor Screen Reveals Protein Kinase C-dependent Endocytic Recycling of ErbB2 in Breast Cancer Cells*

  2014influential reference
• Crystal structure of PfRh5, an essential P. falciparum ligand for invasion of human erythrocytes

  2014influential reference
• The Merozoite Surface Protein 1 Complex Is a Platform for Binding to Human Erythrocytes by Plasmodium falciparum*

  2014influential reference
• Malaria adhesins: structure and function

  2014cited by this paper
• Multimeric Assembly of Host-Pathogen Adhesion Complexes Involved in Apicomplexan Invasion

  2014cited by this paper
• Ultrasensitive proteome analysis using paramagnetic bead technology

  2014influential reference
• If cell mechanics can be described by elastic modulus: study of different models and probes used in indentation experiments.

  2014influential reference
• A quantitative assay for binding and inhibition of Plasmodium falciparum Erythrocyte Binding Antigen 175 reveals high affinity binding depends on both DBL domains.

  2014cited by this paper
• Spleen tyrosine kinase inhibitors: a review of the patent literature 2010 – 2013

  2014cited by this paper
• A Sphingosine-1 Phosphate Agonist (FTY720) Limits Trauma/Hemorrhagic Shock–Induced Multiple Organ Dysfunction Syndrome

  2014cited by this paper
• The AMPK Inhibitor Compound C Is a Potent AMPK-Independent Antiglioma Agent

  2014cited by this paper
• The Functional Significance of the Rho/Rho-Kinase Pathway in Human Erythrocytes

  2014cited by this paper
• Sphingosine and FTY720 are potent inhibitors of the transient receptor potential melastatin 7 (TRPM7) channels

  2013cited by this paper
• Simvastatin and GGTI-2133, a geranylgeranyl transferase inhibitor, increase erythrocyte deformability but reduce low O(2) tension-induced ATP release.

  2013cited by this paper
• Vaccination with Conserved Regions of Erythrocyte-Binding Antigens Induces Neutralizing Antibodies against Multiple Strains of Plasmodium falciparum

  2013influential reference
• Role molecular signaling pathways in changes of red blood cell deformability

  2013cited by this paper
• Molecular Basis for Sialic Acid-dependent Receptor Recognition by the Plasmodium falciparum Invasion Protein Erythrocyte-binding Antigen-140/BAEBL*

  2013cited by this paper
• Structural and Functional Basis for Inhibition of Erythrocyte Invasion by Antibodies that Target Plasmodium falciparum EBA-175

  2013influential reference
• Identification of a Novel Role for Dematin in Regulating Red Cell Membrane Function by Modulating Spectrin-Actin Interaction*

  2012cited by this paper
• A robust permutation test for quantitative SILAC proteomics experiments

  2012cited by this paper
• The conductance of red blood cells from sickle cell patients: ion selectivity and inhibitors

  2012cited by this paper
• Natural and synthetic modulators of SK (Kca2) potassium channels inhibit magnesium‐dependent activity of the kinase‐coupled cation channel TRPM7

  2012cited by this paper
• Detailed examination of Mg2+ and pH sensitivity of human TRPM7 channels.

  2012cited by this paper
• Insights into Duffy Binding-like Domains through the Crystal Structure and Function of the Merozoite Surface Protein MSPDBL2 from Plasmodium falciparum*

  2012influential reference
• Crystal and Solution Structures of Plasmodium falciparum Erythrocyte-binding Antigen 140 Reveal Determinants of Receptor Specificity during Erythrocyte Invasion*

  2012cited by this paper
• Waixenicin A Inhibits Cell Proliferation through Magnesium-dependent Block of Transient Receptor Potential Melastatin 7 (TRPM7) Channels*

  2011influential reference
• BASIGIN is a receptor essential for erythrocyte invasion by Plasmodium falciparum

  2011cited by this paper
• Cytoskeletal and membrane remodelling during malaria parasite invasion of the human erythrocyte

  2011cited by this paper
• Delineation of Stage Specific Expression of Plasmodium falciparum EBA-175 by Biologically Functional Region II Monoclonal Antibodies

  2011influential reference
• Lipid A decreases human erythrocytes deformability by increasing intracellular Ca2+: Effects of verapamil, staurosporine and the rho-kinase inhibitor Y-27632

  2011influential reference
• Ligation of complement receptor 1 increases erythrocyte membrane deformability.

  2010cited by this paper
• Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand

  2010influential reference
• Tropomodulin 1-null mice have a mild spherocytic elliptocytosis with appearance of tropomodulin 3 in red blood cells and disruption of the membrane skeleton.

  2010cited by this paper
• Interactions with heparin-like molecules during erythrocyte invasion by Plasmodium falciparum merozoites.

  2010cited by this paper
• Reticulocyte and Erythrocyte Binding-Like Proteins Function Cooperatively in Invasion of Human Erythrocytes by Malaria Parasites

  2010influential reference
• In-depth Qualitative and Quantitative Profiling of Tyrosine Phosphorylation Using a Combination of Phosphopeptide Immunoaffinity Purification and Stable Isotope Dimethyl Labeling*

  2009cited by this paper
• Red blood cell-deformability measurement: Review of techniques

  2009cited by this paper
• Antibodies to Reticulocyte Binding Protein-Like Homologue 4 Inhibit Invasion of Plasmodium falciparum into Human Erythrocytes

  2009cited by this paper
• Morphology and kinetics of the three distinct phases of red blood cell invasion by Plasmodium falciparum merozoites.

  2009cited by this paper
• Multiplex peptide stable isotope dimethyl labeling for quantitative proteomics

  2009cited by this paper
• Reticulocyte-binding protein homologue 5 - an essential adhesin involved in invasion of human erythrocytes by Plasmodium falciparum.

  2009cited by this paper
• Effect of mutations imitating the phosphorylation by TRPM7 kinase on the function of the N-terminal domain of tropomodulin

  2008influential reference
• MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification

  2008cited by this paper
• Red cell membrane: past, present, and future.

  2008influential reference
• SIMAC (Sequential Elution from IMAC), a Phosphoproteomics Strategy for the Rapid Separation of Monophosphorylated from Multiply Phosphorylated Peptides*S

  2008cited by this paper
• Erythrocyte binding protein PfRH5 polymorphisms determine species-specific pathways of Plasmodium falciparum invasion.

  2008cited by this paper
• Cytoskeletal dynamics of human erythrocyte

  2007cited by this paper
• Activation of TRPM7 Channels by Phospholipase C-coupled Receptor Agonists*

  2007cited by this paper
• Development and Optimization of High-Throughput Methods To Measure Plasmodium falciparum-Specific Growth Inhibitory Antibodies

  2006cited by this paper
• TRPM7, a novel regulator of actomyosin contractility and cell adhesion

  2006cited by this paper
• Structural basis for the EBA-175 erythrocyte invasion pathway of the malaria parasite Plasmodium falciparum.

  2005influential reference
• Modulation of Erythrocyte Membrane Mechanical Function by Protein 4.1 Phosphorylation*

  2005cited by this paper
• Molecular Mechanism for Switching of P. falciparum Invasion Pathways into Human Erythrocytes

  2005cited by this paper
• Characterization of the Protein Kinase Activity of TRPM7/ChaK1, a Protein Kinase Fused to the Transient Receptor Potential Ion Channel*

  2004influential reference
• Phosphorylation of Annexin I by TRPM7 Channel-Kinase*

  2004cited by this paper
• Phenotypic variation of Plasmodium falciparum merozoite proteins directs receptor targeting for invasion of human erythrocytes

  2003influential reference
• Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations

  2003influential reference
• Distinct Mechanosensitive Properties of Capsaicin-Sensitive and -Insensitive Sensory Neurons

  2002cited by this paper
• Identification of Proteins from Plasmodium falciparum That Are Homologous to Reticulocyte Binding Proteins inPlasmodium vivax

  2001cited by this paper
• An expanding ebl family of Plasmodium falciparum.

  2001influential reference
• Red cell antigens on band 3 and glycophorin A.

  2000influential reference
• Two Plasmodium falciparum genes express merozoite proteins that are related to Plasmodium vivax and Plasmodium yoelii adhesive proteins involved in host cell selection and invasion.

  2000cited by this paper
• Receptor and ligand domains for invasion of erythrocytes by Plasmodium falciparum.

  1994cited by this paper
• Quantitation of the number of molecules of glycophorins C and D on normal red blood cells using radioiodinated Fab fragments of monoclonal antibodies.

  1994cited by this paper
• Tropomodulin caps the pointed ends of actin filaments

  1994cited by this paper
• A malaria invasion receptor, the 175-kilodalton erythrocyte binding antigen of Plasmodium falciparum recognizes the terminal Neu5Ac(alpha 2- 3)Gal- sequences of glycophorin A

  1992cited by this paper
• Identification of a restriction fragment length polymorphism by a CR1 cDNA that correlates with the number of CR1 on erythrocytes

  1986cited by this paper
• Physiological shear stresses enhance the Ca2+ permeability of human erythrocytes

  1981cited by this paper
• Release of diacylglycerol-enriched vesicles from erythrocytes with increased intracellular [Ca2+]

  1976cited by this paper
• Drug-induced erythrocyte membrane internalization.

  1972cited by this paper
• TROPICAL MEDICINE AND HYGIENE

  1917influential reference

• Nuclear import of malaria RNA rewires splicing in host immune cells.

  2026cites this paper
• In silico analysis of the invasion mechanics and invasiveness of the plasmodium falciparum merozoite

  2026cites this paper
• CD44 cross-linking promotes Plasmodium falciparum invasion

  2025cites this paper
• Extracellular vesicles in malaria: proteomics insights, in vitro and in vivo studies indicate the need for transitioning to natural human infections

  2025influential citation
• Physiological functions and pharmacological targeting of transient receptor potential channels

  2025cites this paper
• An RBC-MsUQ Framework for Red Blood Cell Morpho-Mechanics

  2025cites this paper
• Plasmodium falciparum exploits NUAK1 to establish infection in human erythrocytes

  2025cites this paper
• CD44 cross-linking promotes Plasmodium falciparum invasion

  2025influential citation
• Transient Receptor Potential Melastatin 7 (TRPM7) Ion Channel Inhibitors: Preliminary SAR and Conformational Studies of Xenicane Diterpenoids from the Hawaiian Soft Coral Sarcothelia edmondsoni.

  2024cites this paper
• Transcriptome analysis reveals molecular targets of erythrocyte invasion phenotype diversity in natural Plasmodium falciparum isolates from Cameroon

  2024cites this paper
• Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules

  2024cites this paper
• Plasmodium falciparum exploits CD44 as a co-receptor for erythrocyte invasion

  2023cites this paper
• Genetic polymorphism and natural selection of the erythrocyte binding antigen 175 region II in Plasmodium falciparum populations from Myanmar and Vietnam

  2023cites this paper
• Basigin mediation of Plasmodium falciparum red blood cell invasion does not require its transmembrane domain or interaction with monocarboxylate transporter 1

  2023cites this paper
• Plasmodium falciparum exploits CD44 as a coreceptor for erythrocyte invasion

  2023cites this paper
• Increased Blood Concentrations of Malondialdehyde in Plasmodium Infection: A Systematic Review and Meta-Analysis

  2023cites this paper
• A constitutive model for the remodelling erythrocyte membrane skeleton during the active invasion by the malaria merozoite

  2023cites this paper
• Effective cell membrane tension protects red blood cells against malaria invasion

  2023cites this paper
• A Review of Major Patents on Potential Malaria Vaccine Targets

  2023cites this paper
• Revisiting the malaria hypothesis: accounting for polygenicity and pleiotropy.

  2022cites this paper
• Generation of red blood cells from stem cells: Achievements, opportunities and perspectives for malaria research

  2022cites this paper
• PdpC, a secreted effector protein of the type six secretion system, is required for erythrocyte invasion by Francisella tularensis LVS

  2022cites this paper
• Inhibition of Plasmodium berghei growth by alkaloid extract of Phyllanthus amarus in mice increased haem level and stabilized erythrocyte membrane

  2022cites this paper
• An analytical model describing the mechanics of erythrocyte membrane wrapping during active invasion of a plasmodium falciparum merozoite

  2022cites this paper
• Biophysical Tools and Concepts Enable Understanding of Asexual Blood Stage Malaria

  2022cites this paper
• RBC membrane biomechanics and Plasmodium falciparum invasion: probing beyond ligand-receptor interactions.

  2022cites this paper
• 20S proteasomes secreted by the malaria parasite promote its growth

  2021cites this paper
• Microfluidic electrical impedance assessment of red blood cell-mediated microvascular occlusion.

  2021cites this paper
• Pharmacological activation of PIEZO1 in human red blood cells prevents Plasmodium falciparum invasion

  2021cites this paper
• 4D analysis of malaria parasite invasion offers insights into erythrocyte membrane remodeling and parasitophorous vacuole formation

  2021cites this paper
• Erythrocyte flow through the interendothelial slits of the splenic venous sinus

  2021cites this paper
• Cholesterol dynamics are essential for the growth and development of Plasmodium falciparum within the erythrocyte

  2021cites this paper
• Sistemas de expresión de proteínas recombinantes para el análisis funcional de antígenos de Plasmodium falciparum y Plasmodium vivax: una revisión

  2021cites this paper
• Alternative Invasion Mechanisms and Host Immune Response to Plasmodium vivax Malaria: Trends and Future Directions

  2020cites this paper
• Red blood cell tension protects against severe malaria in the Dantu blood group

  2020cites this paper
• Hotspots in Plasmodium and RBC Receptor-Ligand Interactions: Key Pieces for Inhibiting Malarial Parasite Invasion

  2020cites this paper
• Actomyosin forces and the energetics of red blood cell invasion by the malaria parasite Plasmodium falciparum

  2020cites this paper
• The Human Spleen in Malaria: Filter or Shelter?

  2020cites this paper
• An Exported Kinase Family Mediates Species-Specific Erythrocyte Remodelling and Virulence in Human Malaria

  2020cites this paper
• Role of RBC membrane protein palmitoylation in regulation of molecular topology and susceptibility to Plasmodium falciparum invasion

  2020cites this paper
• Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle

  2020cites this paper
• Red blood cell tension protects against severe malaria in the Dantu blood group

  2020cites this paper
• Methods to Investigate the Deformability of RBC During Malaria

  2020cites this paper
• Mapping TRPM7 Function by NS8593

  2020cites this paper
• Waixenicin A, a marine-derived TRPM7 inhibitor: a promising CNS drug lead

  2020cites this paper
• Protein modification characteristics of the malaria parasite Plasmodium falciparum and the infected erythrocytes.

  2020cites this paper
• Plasmodium falciparum maturation across the intra-erythrocytic cycle shifts the soft glassy viscoelastic properties of red blood cells from a liquid-like towards a solid-like behavior.

  2020cites this paper
• A review of the biomechanical properties of single extracellular vesicles

  2020cites this paper
• Protein Modification Characteristics of the Malaria Parasite Plasmodium falciparum and the Infected Erythrocytes

  2020cites this paper
• Epsilon-Genic Effects Bridge the Gap Between Polygenic and Omnigenic Complex Traits

  2019cites this paper
• Blood-Stage Malaria Parasite Antigens: Structure, Function, and Vaccine Potential.

  2019cites this paper
• Estudio del efecto de péptidos sintéticos derivados de proteínas de Plasmodium falciparum sobre el flujo de calcio en glóbulos rojos

  2019cites this paper
• Host Cytoskeleton Remodeling throughout the Blood Stages of Plasmodium falciparum

  2019cites this paper
• Erythrocyte glycophorins as receptors for Plasmodium merozoites

  2019cites this paper
• The effects of dyslipidaemia and cholesterol modulation on erythrocyte susceptibility to malaria parasite infection

  2019cites this paper
• Nonlinear Biomechanical Characteristics of Deep Deformation of Native RBC Membranes in Normal State and under Modifier Action

  2018cites this paper
• Genetic structure of two erythrocyte binding antigens of Plasmodium falciparum reveals a contrasting pattern of selection.

  2018cites this paper
• Evidence against a Role of Elevated Intracellular Ca2+ during Plasmodium falciparum Preinvasion.

  2018cites this paper
• Extending the Compatibility of the SP3 Paramagnetic Bead Processing Approach for Proteomics.

  2018cites this paper
• Analysis of exported proteins and parasite-induced host cell rigidity changes during the Plasmodium falciparum intraerythrocxytic life cycle

  2018cites this paper
• Red blood cell tension controls Plasmodium falciparum invasion and protects against severe malaria in the Dantu blood group

  2018cites this paper
• Shed EBA-175 mediates red blood cell clustering that enhances malaria parasite growth and enables immune evasion

  2018cites this paper
• Shelph2, a bacterial-like phosphatase of the malaria parasite Plasmodium falciparum, is dispensable during asexual blood stage

  2017cites this paper
• Molecular mechanisms of deformability of Plasmodium-infected erythrocytes.

  2017cites this paper
• Assessment of TRPM7 functions by drug-like small molecules.

  2017cites this paper
• The Molecular Basis of Erythrocyte Invasion by Malaria Parasites.

  2017cites this paper
• Gliding motility powers invasion and egress in Apicomplexa

  2017cites this paper
• Genetic Evidence for Erythrocyte Receptor Glycophorin B Expression Levels Defining a Dominant Plasmodium falciparum Invasion Pathway into Human Erythrocytes

  2017cites this paper
• Host iron status and erythropoietic response to iron supplementation determines susceptibility to the RBC stage of falciparum malaria during pregnancy

  2017cites this paper