Plasmodium falciparum LipB mutants display altered redox and carbon metabolism in asexual stages and cannot complete sporogony in Anopheles mosquitoes

Biddau, M. et al. (2021) Plasmodium falciparum LipB mutants display altered redox and carbon metabolism in asexual stages and cannot complete sporogony in Anopheles mosquitoes. International Journal for Parasitology, 51(6), pp. 441-453. (doi: 10.1016/j.ijpara.2020.10.011) (PMID:33713652) (PMCID:PMC8126644)

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Abstract

Malaria is still one of the most important global infectious diseases. Emergence of drug resistance and a shortage of new efficient antimalarials continue to hamper a malaria eradication agenda. Malaria parasites are highly sensitive to changes in the redox environment. Understanding the mechanisms regulating parasite redox could contribute to the design of new drugs. Malaria parasites have a complex network of redox regulatory systems housed in their cytosol, in their mitochondrion and in their plastid (apicoplast). While the roles of enzymes of the thioredoxin and glutathione pathways in parasite survival have been explored, the antioxidant role of α-lipoic acid (LA) produced in the apicoplast has not been tested. To take a first step in teasing a putative role of LA in redox regulation, we analysed a mutant Plasmodium falciparum (3D7 strain) lacking the apicoplast lipoic acid protein ligase B (lipB) known to be depleted of LA. Our results showed a change in expression of redox regulators in the apicoplast and the cytosol. We further detected a change in parasite central carbon metabolism, with lipB deletion resulting in changes to glycolysis and tricarboxylic acid cycle activity. Further, in another Plasmodium cell line (NF54), deletion of lipB impacted development in the mosquito, preventing the detection of infectious sporozoite stages. While it is not clear at this point if the observed phenotypes are linked, these findings flag LA biosynthesis as an important subject for further study in the context of redox regulation in asexual stages, and point to LipB as a potential target for the development of new transmission drugs.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Biddau, Dr Marco and Blackburn, Dr Gavin and Sheiner, Dr Lilach and Barrett, Professor Michael
Authors: Biddau, M., Santha Kumar, T.R., Henrich, P., Laine, L. M., Blackburn, G. J., Chokkathukalam, A., Li, T., Lee Sim, K., King, L., Hoffman, S. L., Barrett, M. P., Coombs, G. H., McFadden, G. I., Fidock, D. A., Müller, S., and Sheiner, L.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:International Journal for Parasitology
Publisher:Elsevier
ISSN:0020-7519
ISSN (Online):1879-0135
Published Online:11 March 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in International Journal for Parasitology 51(6): 441-453
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
163108Towards the establishment of a permanent European Virtual Institutededicated to Malaria Research (EVIMalaR)Andrew WatersEuropean Commission (EC)242095III - EVIMALAR
190590ParaMet - A systematic approach to understanding parasite metabolism.Sylke MullerEuropean Commission (EC)ParaMet290080-FP7III - EVIMALAR
305129How do REDox regulators control Apicoplast functions in the parasites causing TOxoplasmosis and MalariaLilach SheinerMedical Research Council (MRC)MR/S024573/1III - Parasitology
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZRIII - Parasitology