A lipocalin mediates unidirectional heme biomineralization in malaria parasites

Abstract

During blood-stage development, malaria parasites are challenged with the detoxification of enormous amounts of heme released during the proteolytic catabolism of erythrocytic hemoglobin. They tackle this problem by sequestering heme into bioinert crystals known as hemozoin. The mechanisms underlying this biomineralization process remain enigmatic. Here, we demonstrate that both rodent and human malaria parasite species secrete and internalize a lipocalin-like protein, PV5, to control heme crystallization. Transcriptional deregulation ofPV5in the rodent parasitePlasmodium bergheiresults in inordinate elongation of hemozoin crystals, while conditionalPV5inactivation in the human malaria agentPlasmodium falciparumcauses excessive multidirectional crystal branching. Although hemoglobin processing remains unaffected, PV5-deficient parasites generate less hemozoin. Electron diffraction analysis indicates that despite the distinct changes in crystal morphology, neither the crystalline order nor unit cell of hemozoin are affected by impaired PV5 function. Deregulation ofPV5expression rendersP. bergheihypersensitive to the antimalarial drugs artesunate, chloroquine, and atovaquone, resulting in accelerated parasite clearance following drug treatment in vivo. Together, our findings demonstrate thePlasmodium-tailored role of a lipocalin family member in hemozoin formation and underscore the heme biomineralization pathway as an attractive target for therapeutic exploitation.

Malaria Pigment Crystals: The Achilles′ Heel of the Malaria Parasite

“…This analysis suggested that coupling exists between the rate of hemoglobin digestion and the rate of heme dimerization and crystallization. This feedback model is supported by a recent publication on the role played by a lipocalin‐like protein, PV5, to control heme crystallization from rodent and human malaria parasites [42] . A knockout of the protein in the human malaria parasite causes what the authors describe as excessive directional branching, indeed what appears to be uncontrolled hemozoin precipitation.…”

“…This model is supported by the role played by a lipocalin-like protein, PV5, to control heme crystallization in rodent and human malaria parasites. [42] The structure of synthetic hemozoin comprises 3 or 4 different isomeric dimers. [44] A subset thereof may act as crystalline self-poisoners on growth, in agreement with the lath habit of synthetic hemozoin.…”

“…This feedback model is supported by a recent publication on the role played by a lipocalin-like protein, PV5, to control heme crystallization from rodent and human malaria parasites. [42] A knockout of the protein in the human malaria parasite causes what the authors describe as excessive directional branching, indeed what appears to be uncontrolled hemozoin precipitation. Interference with the PV5 expression in the rodent malaria parasite leads to a bootlike shape of the hemozoin crystals, (Figure 7).…”

“…The inset is taken from ref. [42], published under Creative Commons Attribution License 4.0.…”

“…This habit is simulated by twinning the crystal structure across its {011} plane and is shown superimposed onto the boot. The inset is taken from ref [42],. published under Creative Commons Attribution License 4.0.…”