Files and links (1)
Published, Version of Record (VoR)CC BY V4.0, Open
Journal article
Na+ Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum
PLoS pathogens, v 12(5), pp e1005647-e1005647
May 2016
PMID: 27227970
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
Metrics
Details
- Title
- Na+ Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum
- Creators
- Sudipta Das - Drexel UniversitySuyash Bhatanagar - Drexel UniversityJoanne M Morrisey - Drexel UniversityThomas M Daly - Drexel UniversityJames M Burns, Jr - Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of AmericaIsabelle Coppens - Johns Hopkins UniversityAkhil B Vaidya - Drexel University
- Publication Details
- PLoS pathogens, v 12(5), pp e1005647-e1005647
- Publisher
- Public LIbrary of Science (PLOS)
- Grant note
- R01 AI098413 / NIAID NIH HHS R01 AI028398 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000379344500037
- Scopus ID
- 2-s2.0-84973345447
- Other Identifier
- 991019168785004721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Microbiology
- Parasitology
- Virology