CXCR4 regulates Plasmodium development in mouse and human hepatocytes

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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Plasmodium Falciparum Parasite Development in Humanized Mice: Liver And Blood Stages

Humanized Mice for HIV Research ◽

10.1007/978-1-4939-1655-9_41 ◽

2014 ◽

pp. 519-528

Author(s):

Till Strowig ◽

Alexander Ploss

Keyword(s):

Plasmodium Falciparum ◽

Humanized Mice ◽

Parasite Development ◽

Plasmodium Falciparum Parasite ◽

Mice Liver ◽

Falciparum Parasite

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A Plasmodium yoelii Mei2-Like RNA Binding Protein Is Essential for Completion of Liver Stage Schizogony

Infection and Immunity ◽

10.1128/iai.01417-15 ◽

2016 ◽

Vol 84 (5) ◽

pp. 1336-1345 ◽

Cited By ~ 8

Author(s):

Dorender A. Dankwa ◽

Marshall J. Davis ◽

Stefan H. I. Kappe ◽

Ashley M. Vaughan

Keyword(s):

Rna Binding ◽

Rna Binding Proteins ◽

Plasmodium Yoelii ◽

Parasite Development ◽

Mammalian Host ◽

Mosquito Vector ◽

Wild Type ◽

Liver Stage ◽

Content Type ◽

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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Association of Plasmodium berghei With the Apical Domain of Hepatocytes Is Necessary for the Parasite's Liver Stage Development

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2019.00451 ◽

2020 ◽

Vol 9 ◽

Author(s):

Lakshmi Balasubramanian ◽

Vanessa Zuzarte-Luís ◽

Tabish Syed ◽

Debakshi Mullick ◽

Saptarathi Deb ◽

...

Keyword(s):

Plasmodium Berghei ◽

Liver Stage ◽

Apical Domain ◽

Stage Development

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Sequestration of cholesterol within the host late endocytic pathway restricts liver-stage Plasmodium development

Molecular Biology of the Cell ◽

10.1091/mbc.e16-07-0531 ◽

2017 ◽

Vol 28 (6) ◽

pp. 726-735 ◽

Cited By ~ 15

Author(s):

Wiebke Petersen ◽

Werner Stenzel ◽

Olivier Silvie ◽

Judith Blanz ◽

Paul Saftig ◽

...

Keyword(s):

Parasitophorous Vacuole ◽

Parasite Burden ◽

Endocytic Pathway ◽

Host Cells ◽

Parasite Development ◽

Liver Stage ◽

Niemann Pick ◽

Development Analysis ◽

Endocytic Compartments

While lysosomes are degradative compartments and one of the defenses against invading pathogens, they are also hubs of metabolic activity. Late endocytic compartments accumulate around Plasmodium berghei liver-stage parasites during development, and whether this is a host defense strategy or active recruitment by the parasites is unknown. In support of the latter hypothesis, we observed that the recruitment of host late endosomes (LEs) and lysosomes is reduced in uis4− parasites, which lack a parasitophorous vacuole membrane protein and arrest during liver-stage development. Analysis of parasite development in host cells deficient for late endosomal or lysosomal proteins revealed that the Niemann–Pick type C (NPC) proteins, which are involved in cholesterol export from LEs, and the lysosome-associated membrane proteins (LAMP) 1 and 2 are important for robust liver-stage P. berghei growth. Using the compound U18666A, which leads to cholesterol sequestration in LEs similar to that seen in NPC- and LAMP-deficient cells, we show that the restriction of parasite growth depends on cholesterol sequestration and that targeting this process can reduce parasite burden in vivo. Taken together, these data reveal that proper LE and lysosome function positively contributes to liver-stage Plasmodium development.

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