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

Wiebke Petersen, Werner Stenzel, Olivier Silvie, Judith Blanz, Paul Saftig, Kai Matuschewski, Alyssa Ingmundson*

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)726-735
Number of pages10
JournalMolecular biology of the cell
Volume28
Issue number6
DOIs
StatePublished - Mar 15 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Petersen, W., Stenzel, W., Silvie, O., Blanz, J., Saftig, P., Matuschewski, K., & Ingmundson, A. (2017). Sequestration of cholesterol within the host late endocytic pathway restricts liver-stage plasmodium development. Molecular biology of the cell, 28(6), 726-735. https://doi.org/10.1091/mbc.E16-07-0531