Intracellular Survival of Leishmania major Depends on Uptake and Degradation of Extracellular Matrix Glycosaminoglycans by Macrophages

PLoS Pathogens
Thomas NadererMalcolm J McConville

Abstract

Leishmania parasites replicate within the phagolysosome compartment of mammalian macrophages. Although Leishmania depend on sugars as a major carbon source during infections, the nutrient composition of the phagolysosome remains poorly described. To determine the origin of the sugar carbon source in macrophage phagolysosomes, we have generated a N-acetylglucosamine acetyltransferase (GNAT) deficient Leishmania major mutant (∆gnat) that is auxotrophic for the amino sugar, N-acetylglucosamine (GlcNAc). This mutant was unable to grow or survive in ex vivo infected macrophages even when macrophages were cultivated in presence of exogenous GlcNAc. In contrast, the L. major ∆gnat mutant induced normal skin lesions in mice, suggesting that these parasites have access to GlcNAc in tissue macrophages. Intracellular growth of the mutant in ex vivo infected macrophages was restored by supplementation of the macrophage medium with hyaluronan, a GlcNAc-rich extracellular matrix glycosaminoglycan. Hyaluronan is present and constitutively turned-over in Leishmania-induced skin lesions and is efficiently internalized into Leishmania containing phagolysosomes. These findings suggest that the constitutive internalization and degradation of host ...Continue Reading

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Citations

Nov 21, 2015·The FEBS Journal·Vanessa Liévin-Le Moal, Philippe M Loiseau
Feb 8, 2018·Molecular Microbiology·Eleanor C SaundersMalcolm J McConville
Nov 26, 2015·F1000Research·Malcolm J McConvilleMichael J Dagley
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Aug 12, 2020·Immunology and Cell Biology·Eleanor C Saunders, Malcolm J McConville
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Aug 3, 2021·Current Opinion in Microbiology·Eleanor C SaundersMalcolm J McConville
Aug 14, 2021·Microbiological Research·Sekhu AnsariAsis Datta
Aug 27, 2021·Current Opinion in Microbiology·Carolina FerreiraRicardo Silvestre

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Methods Mentioned

BETA
PCR
fluorescence microscopy
size exclusion chromatography

Software Mentioned

Agilent Mass Hunter
BOXSHADE
AXIOVISION
Mass Hunter
Agilent MassHunter
COFFEE

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