Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection

Manlio Di Cristina, Zhicheng Dou, Matteo Lunghi, Geetha Kannan, My Hang Huynh, Olivia L. McGovern, Tracey L. Schultz, Aric J. Schultz, Alyssa J. Miller, Beth M. Hayes, Wouter Van Der Linden, Carla Emiliani, Matthew Bogyo, Sébastien Besteiro, Isabelle Coppens, Vern B. Carruthers

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number17096
JournalNature microbiology
Volume2
DOIs
StatePublished - Jun 19 2017

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

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  • Cite this

    Di Cristina, M., Dou, Z., Lunghi, M., Kannan, G., Huynh, M. H., McGovern, O. L., Schultz, T. L., Schultz, A. J., Miller, A. J., Hayes, B. M., Van Der Linden, W., Emiliani, C., Bogyo, M., Besteiro, S., Coppens, I., & Carruthers, V. B. (2017). Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection. Nature microbiology, 2, [17096]. https://doi.org/10.1038/nmicrobiol.2017.96