Plasmodium's bottomless pit: properties and functions of the malaria parasite's digestive vacuole.

During intraerythrocytic growth, the human malaria parasite Plasmodium falciparum degrades up to 80% of the host cell's hemoglobin inside an acidified organelle called the digestive vacuole (DV). Here, the globin chains are broken down by a number of proteases, while heme is detoxified through biomineralization, a process that is targeted by several potent antimalarial drugs. This review explores our current understanding of the DV, including the digestion of hemoglobin, the sequestration of heme, and the functions of lipids and transporters of the DV membrane. Furthermore, the mechanisms of drug action inside the DV and the molecular adaptations that mediate resistance are discussed.

Plasmodium Para-Aminobenzoate Synthesis and Salvage Resolve Avoidance of Folate Competition and Adaptation to Host Diet.

Folate metabolism is essential for DNA synthesis and a validated drug target in fast-growing cell populations, including tumors and malaria parasites. Genome data suggest that Plasmodium has retained its capacity to generate folates de novo. However, the metabolic plasticity of folate uptake and biosynthesis by the malaria parasite remains unresolved. Here, we demonstrate that Plasmodium uses an aminodeoxychorismate synthase and an aminodeoxychorismate lyase to promote the biogenesis of the central folate precursor para-aminobenzoate (pABA) in the cytoplasm. We show that the parasite depends on de novo folate synthesis only when dietary intake of pABA by the mammalian host is restricted and that only pABA, rather than fully formed folate, is taken up efficiently. This adaptation, which readily adjusts infection to highly variable pABA levels in the mammalian diet, is specific to blood stages and may have evolved to avoid folate competition between the parasite and its host.

An in silico down-scaling approach uncovers novel constituents of the Plasmodium-containing vacuole.

During blood stage development the malaria parasite resides in a membrane-bound compartment, termed the parasitophorous vacuole (PV). The reasons for this intravacuolar life style and the molecular functions of this parasite-specific compartment remain poorly defined, which is mainly due to our limited knowledge about the molecular make-up of this unique niche. We used an in silico down-scaling approach to select for Plasmodium-specific candidates that harbour signatures of PV residency. Live co-localisation of five endogenously tagged proteins confirmed expression in the PV of Plasmodium berghei blood and liver stages. ER retention was ruled out by addition of the respective carboxyterminal tetrapeptides to a secreted reporter protein. Although all five PV proteins are highly expressed, four proved to be dispensable for parasite development in the mammalian and mosquito host, as revealed by targeted gene deletion. In good agreement with their redundant roles, the knockout parasites displayed no detectable deficiencies in protein export, sequestration, or PV morphology. Together, our approach improved the catalogue of the Plasmodium PV proteome and provides experimental genetics evidence for functional redundancy of several PV proteins.

An Unusual Prohibitin Regulates Malaria Parasite Mitochondrial Membrane Potential.

Proteins of the stomatin/prohibitin/flotillin/HfIK/C (SPFH) family are membrane-anchored and perform diverse cellular functions in different organelles. Here, we investigate the SPFH proteins of the murine malaria model parasite Plasmodium berghei, the conserved prohibitin 1, prohibitin 2, and stomatin-like protein and an unusual prohibitin-like protein (PHBL). The SPFH proteins localize to the parasite mitochondrion. While the conserved family members could not be deleted from the Plasmodium genome, PHBL was successfully ablated, resulting in impaired parasite fitness and attenuated virulence in the mammalian host. Strikingly, PHBL-deficient parasites fail to colonize the Anopheles vector because of complete arrest during ookinete development in vivo. We show that this arrest correlates with depolarization of the mitochondrial membrane potential (ΔΨmt). Our results underline the importance of SPFH proteins in the regulation of core mitochondrial functions and suggest that fine-tuning of ΔΨmt in malarial parasites is critical for colonization of the definitive host.