The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission

Vega-Rodriguez, J., Franke-Fayard, B., Dinglasan, R.R., Janse, C.J., Pastrana-Mena, R., Rodriguez-Orengo, J.F., Jacobs-Lorena, M., Serrano, A.E., Waters, A. and Srinivasan, P. (2009) The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission. PLoS Pathogens, 5(2), e1000302. (doi: 10.1371/journal.ppat.1000302)

Abstract

1Infection 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.

• Item Type: Articles
• Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Waters, Professor Andy
• Authors: Vega-Rodriguez, J., Franke-Fayard, B., Dinglasan, R.R., Janse, C.J., Pastrana-Mena, R., Rodriguez-Orengo, J.F., Jacobs-Lorena, M., Serrano, A.E., Waters, A., and Srinivasan, P.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: PLoS Pathogens
• Publisher: Public Library of Science
• ISSN: 1553-7366
• ISSN (Online): 1553-7374
• Published Online: 01 January 2009
• Copyright Holders: © 2009 Vega-Rodríguez et al.
• First Published: First published in PLoS Pathogens 2009 5(2): e1000302
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher