A vacuolar lipocalin as a candidate regulator of hemoglobin catabolism and hemozoin formation in the malaria parasite
Cell Biology
Final Report Abstract
During blood stage development, malaria parasites are challenged with the detoxification of enormous amounts of haem released during the proteolytic catabolism of erythrocytic haemoglobin. They tackle this problem by sequestering haem into bioinert crystals known as haemozoin. The mechanisms underlying this biomineralization process remain enigmatic. In this project, I have demonstrated that both rodent and human malaria parasite species secrete and internalize a lipocalin-like protein, PV5, to control haem crystallization. Transcriptional deregulation of PV5 in the rodent parasite Plasmodium berghei results in inordinate elongation of haemozoin crystals, while conditional PV5 inactivation in the human malaria agent Plasmodium falciparum causes excessive multi-directional crystal branching. Although haemoglobin processing remains unaffected, PV5-deficient parasites generate less haemozoin. Electron diffraction analysis indicates that despite the distinct changes in crystal morphology neither the crystalline order nor unit cell of haemozoin are affected by impaired PV5 function. Deregulation of PV5 expression renders P. berghei hypersensitive to the antimalarial drugs artesunate, chloroquine, and atovaquone, resulting in accelerated parasite clearance following drug treatment in vivo. Together, these findings demonstrate the Plasmodium-tailored role of a lipocalin family member in haemozoin formation and underscore the haem biomineralization pathway as an attractive target for therapeutic exploitation. An improved understanding of the mechanisms underlying haem sequestration will provide valuable insights for future drug development efforts.
Publications
- A lipocalin mediates unidirectional heme biomineralization in malaria parasites. PNAS. 2020; 117:16546– 56
Matz JM, Drepper B, Blum TB, van Genderen E, Burrell A, Martin P, Stach T, Collinson L, Abrahams JP, Matuschewski K, Blackman MJ
(See online at https://doi.org/10.1073/pnas.2001153117) - The parasitophorous vacuole of the blood-stage malaria parasite. Nat Rev Microbiol. 2020; 18:379–91
Matz JM, Beck J, Blackman MJ
(See online at https://doi.org/10.1038/s41579-019-0321-3) - An apicoplast-resident folate transporter is essential for sporogony of malaria parasites. Cell Microbiol. 2021; 23:e13266
Korbmacher F, Drepper B, Sanderson T, Martin P, Stach T, Maier AG, Matuschewski K, Matz JM
(See online at https://doi.org/10.1111/cmi.13266)
