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Membrane cholesterol regulates lysosome-plasma membrane fusion events and modulates Trypanosoma cruzi invasion of host cells.

Authors :
Hissa B
Duarte JG
Kelles LF
Santos FP
del Puerto HL
Gazzinelli-Guimarães PH
de Paula AM
Agero U
Mesquita ON
Guatimosim C
Chiari E
Andrade LO
Source :
PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2012; Vol. 6 (3), pp. e1583. Date of Electronic Publication: 2012 Mar 27.
Publication Year :
2012

Abstract

Background: Trypomastigotes of Trypanosoma cruzi are able to invade several types of non-phagocytic cells through a lysosomal dependent mechanism. It has been shown that, during invasion, parasites trigger host cell lysosome exocytosis, which initially occurs at the parasite-host contact site. Acid sphingomyelinase released from lysosomes then induces endocytosis and parasite internalization. Lysosomes continue to fuse with the newly formed parasitophorous vacuole until the parasite is completely enclosed by lysosomal membrane, a process indispensable for a stable infection. Previous work has shown that host membrane cholesterol is also important for the T. cruzi invasion process in both professional (macrophages) and non-professional (epithelial) phagocytic cells. However, the mechanism by which cholesterol-enriched microdomains participate in this process has remained unclear.<br />Methodology/principal Finding: In the present work we show that cardiomyocytes treated with MβCD, a drug able to sequester cholesterol from cell membranes, leads to a 50% reduction in invasion by T. cruzi trypomastigotes, as well as a decrease in the number of recently internalized parasites co-localizing with lysosomal markers. Cholesterol depletion from host membranes was accompanied by a decrease in the labeling of host membrane lipid rafts, as well as excessive lysosome exocytic events during the earlier stages of treatment. Precocious lysosomal exocytosis in MβCD treated cells led to a change in lysosomal distribution, with a reduction in the number of these organelles at the cell periphery, and probably compromises the intracellular pool of lysosomes necessary for T. cruzi invasion.<br />Conclusion/significance: Based on these results, we propose that cholesterol depletion leads to unregulated exocytic events, reducing lysosome availability at the cell cortex and consequently compromise T. cruzi entry into host cells. The results also suggest that two different pools of lysosomes are available in the cell and that cholesterol depletion may modulate the fusion of pre-docked lysosomes at the cell cortex.

Details

Language :
English
ISSN :
1935-2735
Volume :
6
Issue :
3
Database :
MEDLINE
Journal :
PLoS neglected tropical diseases
Publication Type :
Academic Journal
Accession number :
22479662
Full Text :
https://doi.org/10.1371/journal.pntd.0001583