PP1 phosphatase is a key regulator of malaria parasite transmission.

Unlabelled: For the successful transmission of malaria parasites from humans to mosquitoes, gametocytes must remain in the bloodstream long enough to be taken up by a mosquito. Once ingested, they are then activated into gametes to continue the parasite life cycle in the mosquito midgut. Both persistence of gametocytes in the blood and their activation into gametes are tightly regulated by phospho-signaling.

Fetal hemoglobin enables malaria parasite growth in sickle cells but augments production of transmission stage parasites.

Sickle cell trait is the quintessential example of the human evolutionary response to malaria, providing protection against severe disease, but leading to sickle cell disease (SCD) in the homozygous state. Fetal Hemoglobin (HbF) reduces the pathology of SCD and several mutations lead to the prolonged production of HbF into childhood and adult life. HbF has been suggested to contribute to protection against malaria.

The malaria parasite PP1 phosphatase controls the initiation of the egress pathway of asexual blood-stages by regulating the rounding-up of the vacuole.

A sustained blood-stage infection of the human malaria parasite P. falciparum relies on the active exit of merozoites from their host erythrocytes. During this process, named egress, the infected red blood cell undergoes sequential morphological events: the rounding-up of the surrounding parasitophorous vacuole, the disruption of the vacuole membrane and finally the rupture of the red blood cell membrane.

The Anopheles leucine-rich repeat protein APL1C is a pathogen binding factor recognizing Plasmodium ookinetes and sporozoites.

Leucine-rich repeat (LRR) proteins are commonly involved in innate immunity of animals and plants, including for pattern recognition of pathogen-derived elicitors. The Anopheles secreted LRR proteins APL1C and LRIM1 are required for malaria ookinete killing in conjunction with the complement-like TEP1 protein. However, the mechanism of parasite immune recognition by the mosquito remains unclear, although it is known that TEP1 lacks inherent binding specificity.

Phosphodiesterase delta governs the mechanical properties of erythrocytes infected with Plasmodium falciparum gametocytes.

To persist in the blood circulation and to be available for mosquitoes, Plasmodium falciparum gametocytes modify the deformability and the permeability of their erythrocyte host via cyclic AMP (cAMP) signaling pathway. Cyclic nucleotide levels are tightly controlled by phosphodiesterases (PDE), however in Plasmodium these proteins are poorly characterized. Here, we characterize the P.

Erythropoiesis and Malaria, a Multifaceted Interplay.

One of the major pathophysiologies of malaria is the development of anemia. Although hemolysis and splenic clearance are well described as causes of malarial anemia, abnormal erythropoiesis has been observed in malaria patients and may contribute significantly to anemia. The interaction between inadequate erythropoiesis and parasite infection, which partly occurs in the bone marrow, has been poorly investigated to date.

Multiparametric characterization of red blood cell physiology after hypotonic dialysis based drug encapsulation process.

Red blood cells (RBCs) can act as carriers for therapeutic agents and can substantially improve the safety, pharmacokinetics, and pharmacodynamics of many drugs. Maintaining RBCs integrity and lifespan is important for the efficacy of RBCs as drug carrier. We investigated the impact of drug encapsulation by hypotonic dialysis on RBCs physiology and integrity.

The Phosphodiesterase Inhibitor Tadalafil Promotes Splenic Retention Gametocytes in Humanized Mice.

The persistence of erythrocytes infected with gametocytes in the bloodstream is closely related to the modulation of their mechanical properties. New drugs that increase the stiffness of infected erythrocytes may thus represent a novel approach to block malaria parasite transmission. The phosphodiesterase inhibitor tadalafil has been shown to impair the ability of infected erythrocytes to circulate in an model for splenic retention.

Potent Antiplasmodial Derivatives of Dextromethorphan Reveal the -Morphinan Pharmacophore of Tazopsine-Type Alkaloids.

The alkaloid tazopsine was introduced in the late 2000s as a novel antiplasmodial hit compound active against hepatic stages, with the potential to develop prophylactic drugs based on this novel chemical scaffold. However, the structural determinants of tazopsine bioactivity, together with the exact definition of the pharmacophore, remained elusive, impeding further development. We found that the antitussive drug dextromethorphan (DXM) , although lacking the complex pattern of stereospecific functionalization of the natural hit, was harboring significant antiplasmodial activity in vitro despite suboptimal prophylactic activity in a murine model of malaria, precluding its direct repurposing against the disease.

A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites.

Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. For decades, the research for novel antimalarials focused on the high-throughput screening of molecules that only targeted the asexual blood stages. In a search for new effective compounds presenting a triple action against erythrocytic and liver stages in addition to the ability to block the transmission of the disease the mosquito vector, 2-amino-thienopyrimidinone derivatives were synthesized and tested for their antimalarial activity.

Expression Patterns of Plasmodium falciparum Clonally Variant Genes at the Onset of a Blood Infection in Malaria-Naive Humans.

Clonally variant genes (CVGs) play fundamental roles in the adaptation of Plasmodium falciparum to fluctuating conditions of the human host. However, their expression patterns under the natural conditions of the blood circulation have been characterized in detail for only a few specific gene families. Here, we provide a detailed characterization of the complete P.

Tadalafil impacts the mechanical properties of Plasmodium falciparum gametocyte-infected erythrocytes.

Plasmodium falciparum gametocytes modify the mechanical properties of their erythrocyte host to persist for several weeks in the blood circulation and to be available for mosquitoes. These changes are tightly regulated by the plasmodial phosphodiesterase delta that decreases both the stiffness and the permeability of the infected host cell. Here, we address the effect of the phosphodiesterase inhibitor tadalafil on deformability and permeability of gametocyte-infected erythrocytes.

Erythroid cells and malaria parasites: it's a match!

Purpose Of Review: The current review outlines recent discoveries on the infection of erythroid cells by Plasmodium parasites, focusing on the molecular interactions governing the tropism of parasites for their host cell and the implications of this tropism for parasite biology and erythroid cell maturation.

Recent Findings: Although most studies about the interactions of Plasmodium parasites and their host cell focused on the deadliest human malaria parasite, Plasmodium falciparum, and the erythrocyte, there is increasing evidence that several Plasmodium species, including P. falciparum, also develop within erythroid precursors.

Myotonic dystrophy kinase-related CDC42-binding kinase α, a new transferrin receptor type 2-binding partner, is a regulator of erythropoiesis.

Efficient erythropoiesis relies on the expression of the transferrin receptor type 2 (TFR2). In erythroid precursors, TFR2 facilitates the export of the erythropoietin receptor (EPOR) to cell surface, which ensures the survival and proliferation of erythroblasts. Although TFR2 has a crucial role in erythropoiesis regulation, its mechanism of action remains to be clarified.

Plasmodium falciparum sexual parasites regulate infected erythrocyte permeability.

To ensure the transport of nutrients necessary for their survival, Plasmodium falciparum parasites increase erythrocyte permeability to diverse solutes. These new permeation pathways (NPPs) have been extensively characterized in the pathogenic asexual parasite stages, however the existence of NPPs has never been investigated in gametocytes, the sexual stages responsible for transmission to mosquitoes. Here, we show that NPPs are still active in erythrocytes infected with immature gametocytes and that this activity declines along gametocyte maturation.

Increased circulation time of Plasmodium falciparum underlies persistent asymptomatic infection in the dry season.

The dry season is a major challenge for Plasmodium falciparum parasites in many malaria endemic regions, where water availability limits mosquito vectors to only part of the year. How P. falciparum bridges two transmission seasons months apart, without being cleared by the human host or compromising host survival, is poorly understood.

Plasmodium falciparum sexual parasites develop in human erythroblasts and affect erythropoiesis.

Plasmodium falciparum gametocytes, the sexual stage responsible for malaria parasite transmission from humans to mosquitoes, are key targets for malaria elimination. Immature gametocytes develop in the human bone marrow parenchyma, where they accumulate around erythroblastic islands. Notably though, the interactions between gametocytes and this hematopoietic niche have not been investigated.

A Chemically Stable Fluorescent Mimic of Dihydroartemisinin, Artemether, and Arteether with Conserved Bioactivity and Specificity Shows High Pharmacological Relevance to the Antimalarial Drugs.

Three novel tracers designed as fluorescent surrogates of artemisinin-derived antimalarial drugs (i.e., dihydroartemisinin, artemether, arteether, and artemisone) were synthesized from dihydroartemisinin.

Erythrocyte Membrane Makeover by Gametocytes.

sexual parasites, called gametocytes, are the only parasite stages responsible for transmission from humans to mosquitoes. During their maturation, gametocytes remodel the structural and mechanical properties of the membrane of their erythrocyte host. This remodeling is induced by the export of several parasite proteins and a dynamic reorganization of the erythrocyte cytoskeleton.

Plasmodium falciparum gametocyte-infected erythrocytes do not adhere to human primary erythroblasts.

Plasmodium falciparum gametocytes, the sexual stages responsible for malaria parasite transmission, develop in the human bone marrow parenchyma in proximity to the erythroblastic islands. Yet, mechanisms underlying gametocytes interactions with these islands are unknown. Here, we have investigated whether gametocyte-infected erythrocytes (GIE) adhere to erythroid precursors, and whether a putative adhesion may be mediated by a mechanism similar to the adhesion of erythrocytes infected with P.

Humanized mouse models infected with human Plasmodium species for antimalarial drug discovery.

Efforts on malaria drug discovery are expected to increase in the coming years to achieve malaria eradication. Owing to the increasing number of new potential candidates together with the actual limitations of the primate models, humanized mouse models infected with human Plasmodium spp. (HmHP) now appear as an alternative to the primate model.

Molecular mechanisms of deformability of Plasmodium-infected erythrocytes.

In physiological conditions, normal erythrocytes are highly deformable due to their high surface area to volume ratio, their moderate cytoplasmic viscosity and the elasticity of their membrane skeleton. Infection with the human malaria parasite Plasmodium falciparum induces dramatic changes in cellular deformability and membrane elasticity of their host erythrocyte, in part due to the shape and the volume of the parasite itself, and to the export of parasite proteins that interact with host membrane skeletal proteins. These changes in deformability are tightly regulated by the parasite and may reflect a strategy to adapt to mechanical constraints encountered by the parasite in the human host.

Plasmodium Merozoite TRAP Family Protein Is Essential for Vacuole Membrane Disruption and Gamete Egress from Erythrocytes.

Surface-associated TRAP (thrombospondin-related anonymous protein) family proteins are conserved across the phylum of apicomplexan parasites. TRAP proteins are thought to play an integral role in parasite motility and cell invasion by linking the extracellular environment with the parasite submembrane actomyosin motor. Blood stage forms of the malaria parasite Plasmodium express a TRAP family protein called merozoite-TRAP (MTRAP) that has been implicated in erythrocyte invasion.