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Toxoplasma TgATG9 is critical for autophagy and long-term persistence in tissue cysts

David Smith, Geetha Kannan, Isabelle Coppens, Fengrong Wang, Hoa Mai Nguyen, Aude Cerutti, Tracey L. Schultz, Patrick A. Rimple, Manlio Di Cristina, Sébastien Besteiro, Vern B. Carruthers
doi: https://doi.org/10.1101/2020.05.13.093401
David Smith
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, 48109 USA
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  • For correspondence: vcarruth@umich.edu
Geetha Kannan
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, 48109 USA
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Isabelle Coppens
2Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, 21205 USA
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Fengrong Wang
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, 48109 USA
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Hoa Mai Nguyen
3Laboratory of Pathogen Host Interactions, UMR 5235, CNRS, Université de Montpellier, 34095 Montpellier Cedex 5, France
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Aude Cerutti
3Laboratory of Pathogen Host Interactions, UMR 5235, CNRS, Université de Montpellier, 34095 Montpellier Cedex 5, France
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Tracey L. Schultz
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, 48109 USA
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Patrick A. Rimple
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, 48109 USA
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Manlio Di Cristina
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, 48109 USA
4Department of Chemistry, Biology and Biotechnology, Università degli Studi di Perugia, 06122, Perugia, Italy
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Sébastien Besteiro
3Laboratory of Pathogen Host Interactions, UMR 5235, CNRS, Université de Montpellier, 34095 Montpellier Cedex 5, France
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Vern B. Carruthers
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, 48109 USA
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  • For correspondence: vcarruth@umich.edu
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ABSTRACT

Many of the world’s warm-blooded species are chronically infected with Toxoplasma gondii tissue cysts, including up to an estimated one third of the global human population. The cellular processes that permit long-term parasite persistence within the cyst are largely unknown, not only for T. gondii but also for related coccidian parasites that impact human and animal health. A previous study revealed an accumulation of autophagic material in the lysosome-like Vacuolar Compartment (VAC) of chronic stage bradyzoites lacking functional cathepsin L protease (TgCPL) activity. Furthermore, it was shown that TgCPL knockout bradyzoites have compromised viability, indicating the turnover of autophagic material could be necessary for bradyzoite survival. However, the extent to which autophagy itself contributes to bradyzoite development and fitness remained unknown. Herein we show that genetic ablation of TgATG9 substantially reduces canonical autophagy and compromises bradyzoite viability. Transmission electron microscopy revealed structural abnormalities occurring in Δatg9 bradyzoites, including disorganization of the inner membrane complex and plasma membrane, the occurrence of multiple nuclei within a single bradyzoite cell, as well as various anomalies associated with the VAC. TgATG9-deficient bradyzoites accumulated significantly less undigested material in the VAC upon inhibition of TgCPL activity, suggesting that autophagy contributes material to the VAC for degradation. Intriguingly, abnormal mitochondria networks were observed in TgATG9-deficient bradyzoites. They were thin and elongated and often adopted a horseshoe conformation. Some abnormal mitochondrial structures were found to contain numerous different cytoplasmic components and organelles. Bradyzoite fitness was found to be drastically compromised, both in vitro and in mice, with very few brain cysts identified in mice 5 weeks post-infection. Taken together, our data suggests that TgATG9, and by extension autophagy, is critical for cellular homeostasis in bradyzoites and is necessary for long-term persistence within the cyst of this coccidian parasite.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted May 15, 2020.
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Toxoplasma TgATG9 is critical for autophagy and long-term persistence in tissue cysts
David Smith, Geetha Kannan, Isabelle Coppens, Fengrong Wang, Hoa Mai Nguyen, Aude Cerutti, Tracey L. Schultz, Patrick A. Rimple, Manlio Di Cristina, Sébastien Besteiro, Vern B. Carruthers
bioRxiv 2020.05.13.093401; doi: https://doi.org/10.1101/2020.05.13.093401
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Toxoplasma TgATG9 is critical for autophagy and long-term persistence in tissue cysts
David Smith, Geetha Kannan, Isabelle Coppens, Fengrong Wang, Hoa Mai Nguyen, Aude Cerutti, Tracey L. Schultz, Patrick A. Rimple, Manlio Di Cristina, Sébastien Besteiro, Vern B. Carruthers
bioRxiv 2020.05.13.093401; doi: https://doi.org/10.1101/2020.05.13.093401

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