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Nat Microbiol. 2017 Jun 19;2:17096. doi: 10.1038/nmicrobiol.2017.96.

Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection.

Author information

1
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
2
Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia 06122, Italy.
3
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
4
DIMNP-UMR 5235 CNRS, Université de Montpellier, 34095 Montpellier Cedex 5, France.
5
Department of Molecular Microbiology and Immunology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.

Abstract

Globally, nearly 2 billion people are infected with the intracellular protozoan Toxoplasma gondii1. This persistent infection can cause severe disease in immunocompromised people and is epidemiologically linked to major mental illnesses2 and cognitive impairment3. There are currently no options for curing this infection. The lack of effective therapeutics is due partly to a poor understanding of the essential pathways that maintain long-term infection. Although it is known that Toxoplasma replicates slowly within intracellular cysts demarcated with a cyst wall, precisely how it sustains itself and remodels organelles in this niche is unknown. Here, we identify a key role for proteolysis within the parasite lysosomal organelle (the vacuolar compartment or VAC) in turnover of autophagosomes and persistence during neural infection. We found that disrupting a VAC-localized cysteine protease compromised VAC digestive function and markedly reduced chronic infection. Death of parasites lacking the VAC protease was preceded by accumulation of undigested autophagosomes in the parasite cytoplasm. These findings suggest an unanticipated function for parasite lysosomal degradation in chronic infection, and identify an intrinsic role for autophagy in the T. gondii parasite and its close relatives. This work also identifies a key element of Toxoplasma persistence and suggests that VAC proteolysis is a prospective target for pharmacological development.

PMID:
28628099
PMCID:
PMC5527684
DOI:
10.1038/nmicrobiol.2017.96
[Indexed for MEDLINE]
Free PMC Article

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