Plasmodium falciparum ligand binding to erythrocytes induce alterations in deformability essential for invasion
Xavier Sisquella,
Thomas Nebl,
Jennifer K Thompson,
Lachlan Whitehead,
Brian M Malpede,
Nichole D Salinas,
Kelly Rogers,
Niraj H Tolia,
Andrea Fleig,
Joseph O’Neill,
Wai-Hong Tham,
F David Horgen,
Alan F Cowman
Affiliations
Xavier Sisquella
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Thomas Nebl
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Jennifer K Thompson
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Lachlan Whitehead
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Brian M Malpede
Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, St. Louis, United States; Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, United States
Nichole D Salinas
Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, St. Louis, United States; Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, United States
Kelly Rogers
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, St. Louis, United States; Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, United States
Andrea Fleig
The Queen's Medical Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, United States
Joseph O’Neill
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Wai-Hong Tham
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Australia
F David Horgen
Department of Natural Sciences, Hawaii Pacific University, Kaneohe, United States
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Australia
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.
