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

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.

journal_name

Mol Biol Cell

authors

Petersen W,Stenzel W,Silvie O,Blanz J,Saftig P,Matuschewski K,Ingmundson A

doi

10.1091/mbc.E16-07-0531

subject

Has Abstract

pub_date

2017-03-15 00:00:00

pages

726-735

issue

6

eissn

1059-1524

issn

1939-4586

pii

mbc.E16-07-0531

journal_volume

28

pub_type

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