The Glutathione Biosynthetic Pathway of Plasmodium Is Essential for Mosquito Transmission

PLoS Pathogens

Marcelo Jacobs-Lorena¹  Rebecca Pastrana-Mena²  Joel Vega-Rodríguez²  Adelfa E. Serrano³  Rhoel R. Dinglasan³  José F. Rodríguez-Orengo³  Andrew P. Waters⁴  Blandine Franke-Fayard⁴  Chris J. Janse⁴  Isabelle Coppens⁵ 

[1] Department of Biochemistry, University of Puerto Rico, School of Medicine, San Juan, Puerto Rico;Department of Microbiology and Medical Zoology, University of Puerto Rico, School of Medicine, San Juan, Puerto Rico;Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United States of America;Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands;Wellcome Trust Centre of Molecular Parasitology and Division of Infection and Immunity, University of Glasgow, Glasgow, United Kingdom

关键词: Oocysts;    Parasitic diseases;    Plasmodium;    Blood;    Sporozoites;    Mosquitoes;    Malarial parasites;    Mitochondria;   

DOI  :  10.1371/journal.ppat.1000302

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Infection of red blood cells (RBC) subjects the malaria parasite to oxidative stress. Therefore, efficient antioxidant and redox systems are required to prevent damage by reactive oxygen species. Plasmodium spp. have thioredoxin and glutathione (GSH) systems that are thought to play a major role as antioxidants during blood stage infection. In this report, we analyzed a critical component of the GSH biosynthesis pathway using reverse genetics. Plasmodium berghei parasites lacking expression of gamma-glutamylcysteine synthetase (γ-GCS), the rate limiting enzyme in de novo synthesis of GSH, were generated through targeted gene disruption thus demonstrating, quite unexpectedly, that γ-GCS is not essential for blood stage development. Despite a significant reduction in GSH levels, blood stage forms of pbggcs− parasites showed only a defect in growth as compared to wild type. In contrast, a dramatic effect on development of the parasites in the mosquito was observed. Infection of mosquitoes with pbggcs− parasites resulted in reduced numbers of stunted oocysts that did not produce sporozoites. These results have important implications for the design of drugs aiming at interfering with the GSH redox-system in blood stages and demonstrate that de novo synthesis of GSH is pivotal for development of Plasmodium in the mosquito.

【 授权许可】

CC BY