title: Sequestration of cholesterol within the host late endocytic pathway restricts liver-stagePlasmodiumdevelopment.
abstract: While lysosomes are degradative compartments and one of the defenses against invading pathogens, they are also hubs of metabolic activity. Late endocytic compartments accumulate aroundPlasmodium bergheiliver-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 inuis4-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-stageP. bergheigrowth. 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-stagePlasmodiumdevelopment.
authors.affiliation: Molecular Parasitology, Humboldt University, 10115 Berlin, Germany.|Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Petersen
authors.affiliation: Institute for Neuropathology, Charité-Universitätsmedizin, 10117 Berlin, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1135, Centre d'Immunologie et des Maladies Infectieuses, F-75013 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Silvie
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University of Kiel, 24098 Kiel, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Blanz
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University of Kiel, 24098 Kiel, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Molecular Parasitology, Humboldt University, 10115 Berlin, Germany.|Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Matuschewski
authors.affiliation: Molecular Parasitology, Humboldt University, 10115 Berlin, Germany alyssa.ingmundson@hu-berlin.de.|Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Ingmundson
mesh_terms: D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D052556:Niemann-Pick Disease, Type C; D010271:Parasites; D010962:Plasmodium berghei / Q000254:growth & development* / Q000378:metabolism
chemical_list: D000736:Androstenes; D052118:Lysosomal-Associated Membrane Protein 1; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D002784:Cholesterol