title: Na+ Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum.
abstract: Among the several new antimalarials discovered over the past decade are at least three clinical candidate drugs, each with a distinct chemical structure, that disrupt Na+ homeostasis resulting in a rapid increase in intracellular Na+ concentration ([Na+]i) within the erythrocytic stages of Plasmodium falciparum. At present, events triggered by Na+ influx that result in parasite demise are not well-understood. Here we report effects of two such drugs, a pyrazoleamide and a spiroindolone, on intraerythrocytic P. falciparum. Within minutes following the exposure to these drugs, the trophozoite stage parasite, which normally contains little cholesterol, was made permeant by cholesterol-dependent detergents, suggesting it acquired a substantial amount of the lipid. Consistently, the merozoite surface protein 1 and 2 (MSP1 and MSP2), glycosylphosphotidylinositol (GPI)-anchored proteins normally uniformly distributed in the parasite plasma membrane, coalesced into clusters. These alterations were not observed following drug treatment of P. falciparum parasites adapted to grow in a low [Na+] growth medium. Both cholesterol acquisition and MSP1 coalescence were reversible upon the removal of the drugs, implicating an active process of cholesterol exclusion from trophozoites that we hypothesize is inhibited by high [Na+]i. Electron microscopy of drug-treated trophozoites revealed substantial morphological changes normally seen at the later schizont stage including the appearance of partial inner membrane complexes, dense organelles that resemble "rhoptries" and apparent nuclear division. Together these results suggest that [Na+]i disruptor drugs by altering levels of cholesterol in the parasite, dysregulate trophozoite to schizont development and cause parasite demise.
authors.affiliation: Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Das
authors.affiliation: Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Suyash
authors.initials: S
authors.lastname: Bhatanagar
authors.affiliation: Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Morrisey
authors.affiliation: Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Daly
authors.affiliation: Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Burns
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coppens
authors.affiliation: Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Akhil B
authors.initials: AB
authors.lastname: Vaidya
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D015153:Blotting, Western; D002784:Cholesterol / Q000378:metabolism*; D004912:Erythrocytes / Q000469:parasitology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D016778:Malaria, Falciparum / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D002784:Cholesterol; D012964:Sodium