Identification of an AP2-family Protein That Is Critical for Malaria Liver Stage Development

Plasmodiumparasites employ posttranscriptional regulatory mechanisms as their life cycle transitions between host cell invasion and replication within both the mosquito vector and mammalian host. RNA binding proteins (RBPs) provide one mechanism for modulation of RNA function. To explore the role ofPlasmodiumRBPs during parasite replication, we searched for RBPs that might play a role during liver stage development, the parasite stage that exhibits the most extensive growth and replication. We identified a parasite ortholog of theMei2(Meiosisinhibited 2) RBP that is conserved amongPlasmodiumspecies (PlasMei2) and exclusively transcribed in liver stage parasites. Epitope-taggedPlasmodium yoeliiPlasMei2 was expressed only during liver stage schizogony and showed an apparent granular cytoplasmic location. Knockout ofPlasMei2(plasmei2−) inP. yoeliionly affected late liver stage development. TheP. yoeliiplasmei2−liver stage size increased progressively until late in development, similar to wild-type parasite development. However,P. yoeliiplasmei2−liver stage schizonts exhibited an abnormal DNA segregation phenotype and failed to form exoerythrocytic merozoites. Consequently the cellular integrity ofP. yoeliiplasmei2−liver stages became increasingly compromised late in development and the majority ofP. yoeliiplasmei2−underwent cell death by the time wild-type liver stages mature and release merozoites. This resulted in a complete block ofP. yoeliiplasmei2−transition from liver stage to blood stage infection in mice. Our results show for the first time the importance of aPlasmodiumRBP in the coordinated progression of late liver stage schizogony and maturation of new invasive forms.

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Gene expression analysis during liver stage development of Plasmodium

International Journal for Parasitology ◽

10.1016/s0020-7519(02)00183-2 ◽

2002 ◽

Vol 32 (13) ◽

pp. 1551-1557 ◽

Cited By ~ 3

Author(s):

John B. Sacci ◽

Abdu F. Azad

Keyword(s):

Gene Expression ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Liver Stage ◽

Stage Development

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Triterpenoids as inhibitors of Plasmodium liver-stage development

Planta Medica ◽

10.1055/s-0031-1282953 ◽

2011 ◽

Vol 77 (12) ◽

Author(s):

C Ramalhete ◽

A Cruz ◽

S Mulhovo ◽

M Prudêncio ◽

MU Ferreira

Keyword(s):

Liver Stage ◽

Stage Development

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CXCR4 regulates Plasmodium development in mouse and human hepatocytes

Journal of Experimental Medicine ◽

10.1084/jem.20182227 ◽

2019 ◽

Vol 216 (8) ◽

pp. 1733-1748 ◽

Cited By ~ 4

Author(s):

Hironori Bando ◽

Ariel Pradipta ◽

Shiroh Iwanaga ◽

Toru Okamoto ◽

Daisuke Okuzaki ◽

...

Keyword(s):

Pharmacological Intervention ◽

Parasite Development ◽

Morphological Transformation ◽

Liver Stage ◽

Kinase C ◽

Successful Infection ◽

Plasmodium Falciparum Parasite ◽

Stage Development ◽

Falciparum Parasite ◽

Human Plasmodium

The liver stage of the etiological agent of malaria, Plasmodium, is obligatory for successful infection of its various mammalian hosts. Differentiation of the rod-shaped sporozoites of Plasmodium into spherical exoerythrocytic forms (EEFs) via bulbous expansion is essential for parasite development in the liver. However, little is known about the host factors regulating the morphological transformation of Plasmodium sporozoites in this organ. Here, we show that sporozoite differentiation into EEFs in the liver involves protein kinase C ζ–mediated NF-κB activation, which robustly induces the expression of C-X-C chemokine receptor type 4 (CXCR4) in hepatocytes and subsequently elevates intracellular Ca2+ levels, thereby triggering sporozoite transformation into EEFs. Blocking CXCR4 expression by genetic or pharmacological intervention profoundly inhibited the liver-stage development of the Plasmodium berghei rodent malaria parasite and the human Plasmodium falciparum parasite. Collectively, our experiments show that CXCR4 is a key host factor for Plasmodium development in the liver, and CXCR4 warrants further investigation for malaria prophylaxis.

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Open-source discovery of chemical leads for next-generation chemoprotective antimalarials

Science ◽

10.1126/science.aat9446 ◽

2018 ◽

Vol 362 (6419) ◽

pp. eaat9446 ◽

Cited By ~ 35

Author(s):

Yevgeniya Antonova-Koch ◽

Stephan Meister ◽

Matthew Abraham ◽

Madeline R. Luth ◽

Sabine Ottilie ◽

...

Keyword(s):

Inhibitory Concentration ◽

Antimalarial Activity ◽

Target Identification ◽

Symptomatic Relief ◽

Next Generation ◽

Asexual Blood Stage ◽

Liver Stage ◽

Mitochondrial Inhibitors ◽

Stage Development

To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.

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