Lipoic acid biosynthesis is essential forPlasmodium falciparumtransmission and influences redox response and carbon metabolism of parasite asexual blood stages

Abstract

26Malaria is still one of the most important global infectious diseases. Emergence of drug 27 resistance and a shortage of new efficient anti-malarials continue to hamper a malaria 28 eradication agenda. Malaria parasites are highly sensitive to changes in redox environment. 29 Understanding the mechanisms regulating parasite redox could contribute to the design of 30 new drugs. Malaria parasites have a complex network of redox regulatory systems housed in 31 their cytosol, in their mitochondrion and in their plastid (apicoplast). While the roles of enzymes 32 of the thioredoxin and glutathione pathways in parasite survival have been explored, the 33 antioxidant role of α-lipoic acid (LA) produced in the apicoplast has not been tested. We 34 analysed the effects of LA depletion on mutant Plasmodium falciparum lacking the apicoplast 35 lipoic acid protein ligase B (lipB). Our results showed a change in expression of redox 36 regulators in the apicoplast and the cytosol. We further detected a change in parasite central 37 carbon metabolism, with LA depletion influencing glycolysis and tricarboxylic acid cycle 38 activity. Importantly, abrogation of LipB impacted P. falciparum mosquito development, 39 preventing oocyst maturation and production of infectious sporozoite stages, thus flagging LA 40 biosynthesis as a potential target for the development of new transmission drugs. 41 42 INTRODUCTION 43