Functional characterization of phospholipases in the malaria parasite Plasmodium falciparum
Final Report Abstract
The protozoan parasite Plasmodium falciparum is the major cause of disease and death from malaria, which continues to be one of the most important infectious diseases worldwide. For its replication within red blood cells, the parasite depends on a highly active and regulated lipid metabolism. Enzymes involved in lipid metabolic processes such as phospholipases are, therefore, potential drug targets. In this project, we characterized the role of several putative phospholipases during blood stage development of P. falciparum. We revealed that out of the 19 putative phospholipases that show expression evidence in asexual blood stage parasites only one enzyme plays an essential role for asexual blood stage proliferation. This was the phosphoinositide-specific phospholipase C whose conditional inactivation led to a strong phenotype during schizont development and impaired phosphoinositide homeostasis. In addition to this, we revealed an important function of the patatin-like phospholipase 2 (PNPLA2) for mitochondrial function. Parasites lacking this enzyme were impaired in asexual blood stage proliferation, displayed defects in their electron transport chain (ETC) and were hypersensitive to mitochondrion-targeting drugs. Furthermore, PNPLA2-deficient parasites showed differences in the composition of their cardiolipins, a unique class of phospholipids with key roles in mitochondrial functions, and displayed a defect in gametocyte maturation, underlining the importance of a functional ETC for parasite transmission to the mosquito vector. Apart from this work, we identified two putative phospholipases whose disruption impaired either asexual blood stage egress or male gametocyte exflagellation, implicating phospholipase function in these important processes of the parasite. Finally, we identified a choline-releasing glycerophosphodiesterase that likely acts downstream of phospholipase function and performs an essential step in phosphocholine biosynthesis and parasite survival. Altogether, our comprehensive studies on the importance of putative phospholipases for the malaria parasite suggest key functions of these enzymes throughout the parasite life cycle. This highlights them as novel versatile key players in the membrane biology of the malaria parasite and putative new drug targets against this important pathogen.
Publications
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A choline-releasing glycerophosphodiesterase essential for phosphatidylcholine biosynthesis and blood stage development in the malaria parasite. eLife, 11.
Ramaprasad, Abhinay; Burda, Paul-Christian; Calvani, Enrica; Sait, Aaron J.; Palma-Duran, Susana Alejandra; Withers-Martinez, Chrislaine; Hackett, Fiona; Macrae, James; Collinson, Lucy; Gilberger, Tim Wolf & Blackman, Michael J.
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A malaria parasite phospholipase facilitates efficient asexual blood stage egress. PLOS Pathogens, 19(6), e1011449.
Ramaprasad, Abhinay; Burda, Paul-Christian; Koussis, Konstantinos; Thomas, James A.; Pietsch, Emma; Calvani, Enrica; Howell, Steven A.; MacRae, James I.; Snijders, Ambrosius P.; Gilberger, Tim-Wolf & Blackman, Michael J.
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A patatin-like phospholipase is important for mitochondrial function in malaria parasites. mBio, 14(6).
Pietsch, Emma; Ramaprasad, Abhinay; Bielfeld, Sabrina; Wohlfarter, Yvonne; Maco, Bohumil; Niedermüller, Korbinian; Wilcke, Louisa; Kloehn, Joachim; Keller, Markus A.; Soldati-Favre, Dominique; Blackman, Michael J.; Gilberger, Tim-Wolf & Burda, Paul-Christian
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Disruption of a Plasmodium falciparum patatin‐like phospholipase delays male gametocyte exflagellation. Molecular Microbiology, 121(3), 529-542.
Pietsch, Emma; Niedermüller, Korbinian; Andrews, Mia; Meyer, Britta S.; Lenz, Tobias L.; Wilson, Danny W.; Gilberger, Tim‐Wolf & Burda, Paul‐Christian
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Global analysis of putative phospholipases in Plasmodium falciparum reveals an essential role of the phosphoinositide-specific phospholipase C in parasite maturation. mBio.
Burda, Paul-Christian; Ramaprasad, Abhinay; Bielfeld, Sabrina; Pietsch, Emma; Woitalla, Anna; Söhnchen, Christoph; Singh, Mehar Nihal; Strauss, Jan; Sait, Aaron; Collinson, Lucy M.; Schwudke, Dominik; Blackman, Michael J. & Gilberger, Tim-Wolf
