A lipocalin mediates unidirectional haem biomineralization in malaria parasites

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. Here, we demonstrate 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, our 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

A lipocalin mediates unidirectional heme biomineralization in malaria parasites.

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 of PV5 in the rodent parasite Plasmodium berghei results in inordinate elongation of hemozoin crystals, while conditional PV5 inactivation in the human malaria agent Plasmodium falciparum causes 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 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, our findings demonstrate the Plasmodium-tailored role of a lipocalin family member in hemozoin formation and underscore the heme biomineralization pathway as an attractive target for therapeutic exploitation

The ultrastructural morphology of Eimeria tenella exhibits striking natural variation and undergoes significant changes during the first few hours of infection

The data generated during this PhD provides novel insights into the biology of Eimeria parasites: protozoan organisms capable of causing enteric disease in a vast array of animals. Working with Eimeria tenella, a clinically and economically significant pathogen of chickens, I have quantified the fusion dynamics of the refractile bodies. Refractile bodies are non-membrane-bound organelles with immunogenic properties and unknown function. The structural and temporal dynamics of refractile body merger shares striking similarity with that of intrinsically disordered protein-containing droplet organelles; this comparison may help to direct future research into the character and function of these mysterious organelles. In an adjacent project, the organelle numbers and volumes for the E. tenella sporozoite stage were quantified. The resultant data shows a surprisingly high level of variability in cell morphometry; this could be due to genetic/epigenetic factors or may reflect an undiscovered maturation phase. The conoid is a cytoskeletal structure found in many important apicomplexan pathogens and is involved in host cell invasion and parasite motility. I have performed the first high resolution quantitative investigation of three-dimensional conoid structure and show that there is also a considerable level variability in conoid structure. Conoid fibre number was found to vary from 13 to 16 per conoid. This variation was seen in both freshly hatched and post-invasion sporozoites, suggesting that genetic factors are involved. Following analysis of structures within the conoid, my data suggests that secretory organelle protein release occurs through intra-conoidal transport, docking and fusion

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

International audienc