title: Functional alteration of red blood cells by a megadalton protein of Plasmodium falciparum.
abstract: Proteins exported from Plasmodium falciparum parasites into red blood cells (RBCs) interact with the membrane skeleton and contribute to the pathogenesis of malaria. Specifically, exported proteins increase RBC membrane rigidity, decrease deformability, and increase adhesiveness, culminating in intravascular sequestration of infected RBCs (iRBCs). Pf332 is the largest (>1 MDa) known malaria protein exported to the RBC membrane, but its function has not previously been determined. To determine the role of Pf332 in iRBCs, we have engineered and analyzed transgenic parasites with Pf332 either deleted or truncated. Compared with RBCs infected with wild-type parasites, mutants lacking Pf332 were more rigid, were significantly less adhesive to CD36, and showed decreased expression of the major cytoadherence ligand, PfEMP1, on the iRBC surface. These abnormalities were associated with dramatic morphologic changes in Maurer clefts (MCs), which are membrane structures that transport malaria proteins to the RBC membrane. In contrast, RBCs infected with parasites expressing truncated forms of Pf332, although still hyperrigid, showed a normal adhesion profile and morphologically normal MCs. Our results suggest that Pf332 both modulates the level of increased RBC rigidity induced by P falciparum and plays a significant role in adhesion by assisting transport of PfEMP1 to the iRBC surface.
authors.affiliation: Department of Microbiology, National Health and Medical Research Council Program in Malaria, Monash University, Victoria, Australia.
authors.forename: Fiona K
authors.initials: FK
authors.lastname: Glenister
authors.forename: Kate M
authors.initials: KM
authors.lastname: Fernandez
authors.forename: Lev M
authors.initials: LM
authors.lastname: Kats
authors.forename: Eric
authors.initials: E
authors.lastname: Hanssen
authors.forename: Narla
authors.initials: N
authors.lastname: Mohandas
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Brian M
authors.initials: BM
authors.lastname: Cooke
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D021381:Protein Transport; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015800:Protozoan Proteins; C073415:antigen Pf332, Plasmodium