Control of Parasitophorous Vacuole Expansion by LYST/Beige Restricts the Intracellular Growth of Leishmania amazonensis

PLoS Pathogens

Norma W. Andrews¹  Diane M. Ward²  Jerry Kaplan²  Kathleen A. Kennedy³  Alan Aderem³  Chau Huynh⁴  Jude Wilson⁴ 

[1] Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut, United States of America;Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America;Institute for Systems Biology, Seattle, Washington, United States of America;Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, United States of America

关键词: Fibroblasts;    Parasitic diseases;    Amastigotes;    Leishmania;    Protozoan infections;    Lysosomes;    Macrophages;    Host cells;   

DOI  :  10.1371/journal.ppat.1000179

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The intracellular protozoan Leishmania replicates in parasitophorous vacuoles (PV) that share many features with late endosomes/lysosomes. L. amazonensis PVs expand markedly during infections, but the impact of PV size on parasite intracellular survival is still unknown. Here we show that host cells infected with L. amazonensis upregulate transcription of LYST/Beige, which was previously shown to regulate lysosome size. Mutations in LYST/Beige caused further PV expansion and enhanced L. amazonensis replication. In contrast, LYST/Beige overexpression led to small PVs that did not sustain parasite growth. Treatment of LYST/Beige over-expressing cells with vacuolin-1 reversed this phenotype, expanding PVs and promoting parasite growth. The opposite was seen with E-64d, which reduced PV size in LYST-Beige mutant cells and inhibited L. amazonensis replication. Enlarged PVs appear to protect parasites from oxidative damage, since inhibition of nitric oxide synthase had no effect on L. amazonensis viability within large PVs, but enhanced their growth within LYST/Beige-induced small PVs. Thus, the upregulation of LYST/Beige in infected cells functions as a host innate response to limit parasite growth, by reducing PV volume and inhibiting intracellular survival.

【 授权许可】

CC BY