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

  1. David Smith  Is a corresponding author
  2. Geetha Kannan
  3. Isabelle Coppens
  4. Fengrong Wang
  5. Hoa Mai Nguyen
  6. Aude Cerutti
  7. Einar B Olafsson
  8. Patrick A Rimple
  9. Tracey L Schultz
  10. Nayanna M Mercado Soto
  11. Manlio Di Cristina
  12. Sébastien Besteiro
  13. Vern B Carruthers  Is a corresponding author
  1. Moredun Research Institute, United Kingdom
  2. University of Michigan, United States
  3. Johns Hopkins University, United States
  4. Université de Montpellier, France
  5. Università degli Studi di Perugia, Italy

Abstract

Many of the world's warm-blooded species are chronically infected with Toxoplasma gondii tissue cysts, including an estimated one third of the global human population. The cellular processes that permit long-term persistence within the cyst are largely unknown for T. gondii and related coccidian parasites that impact human and animal health. Herein we show that genetic ablation of TgATG9 substantially reduces canonical autophagy and compromises bradyzoite viability. Transmission electron microscopy revealed numerous structural abnormalities occurring in ∆atg9 bradyzoites. Intriguingly, abnormal mitochondrial networks were observed in TgATG9-deficient bradyzoites, some of which contained numerous different cytoplasmic components and organelles. ∆atg9 bradyzoite fitness was drastically compromised 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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

The following previously published data sets were used

Article and author information

Author details

  1. David Smith

    Disease Control, Moredun Research Institute, Penicuik, United Kingdom
    For correspondence
    d.smith@moredun.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5158-0522
  2. Geetha Kannan

    Microbiology and Immunology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Isabelle Coppens

    Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Fengrong Wang

    Microbiology and Immunology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hoa Mai Nguyen

    Laboratory of Pathogen Host Interactions, Université de Montpellier, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Aude Cerutti

    Laboratory of Pathogen Host Interactions, Université de Montpellier, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Einar B Olafsson

    Microbiology and Immunology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Patrick A Rimple

    Microbiology and Immunology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Tracey L Schultz

    Microbiology and Immunology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Nayanna M Mercado Soto

    Microbiology and Immunology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Manlio Di Cristina

    4.Department of Chemistry, Biology and Biotechnology, Università degli Studi di Perugia, Perugia, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4154-5210
  12. Sébastien Besteiro

    Laboratory of Pathogen Host Interactions, Université de Montpellier, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1853-1494
  13. Vern B Carruthers

    Microbiology and Immunology, University of Michigan, Ann Arbor, United States
    For correspondence
    vcarruth@umich.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institutes of Health (R01AI120627)

  • Vern B Carruthers

National Institutes of Health (R01AI060767)

  • Isabelle Coppens

Agence Nationale de la Recherche (ANR-19-CE15-0023)

  • Sébastien Besteiro

Fondation pour la Recherche Médicale (FRM EQ20170336725)

  • Sébastien Besteiro

National Institutes of Health (R25GM086262)

  • Nayanna M Mercado Soto

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Sebastian Lourido, Whitehead Institute for Biomedical Research, United States

Ethics

Animal experimentation: All laboratory animal work in this study was carried out in accordance with policies and guidelines specified by the Office of Laboratory Animal Welfare, the US Department of Agriculture, and the American Association for Accreditation of Laboratory Animal Care (AAALAC). The University of Michigan Committee on the Use and Care of Animals (IACUC) approved the animal protocol used for this study (Animal Welfare Assurance A3114-01, protocol PRO00008638).

Version history

  1. Received: June 1, 2020
  2. Accepted: April 27, 2021
  3. Accepted Manuscript published: April 27, 2021 (version 1)
  4. Version of Record published: May 17, 2021 (version 2)

Copyright

© 2021, Smith et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. David Smith
  2. Geetha Kannan
  3. Isabelle Coppens
  4. Fengrong Wang
  5. Hoa Mai Nguyen
  6. Aude Cerutti
  7. Einar B Olafsson
  8. Patrick A Rimple
  9. Tracey L Schultz
  10. Nayanna M Mercado Soto
  11. Manlio Di Cristina
  12. Sébastien Besteiro
  13. Vern B Carruthers
(2021)
Toxoplasma TgATG9 is critical for autophagy and long-term persistence in tissue cysts
eLife 10:e59384.
https://doi.org/10.7554/eLife.59384

Share this article

https://doi.org/10.7554/eLife.59384

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