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Theileria parasites sequester host eIF5A to escape elimination by host-mediated autophagy

Author

Listed:
  • Marie Villares

    (UMR7126 Epigenetics and Cell Fate)

  • Nelly Lourenço

    (UMR7126 Epigenetics and Cell Fate)

  • Ivan Ktorza

    (UMR7126 Epigenetics and Cell Fate)

  • Jérémy Berthelet

    (UMR7126 Epigenetics and Cell Fate)

  • Aristeidis Panagiotou

    (UMR7126 Epigenetics and Cell Fate)

  • Aurélie Richard

    (UMR7126 Epigenetics and Cell Fate)

  • Angélique Amo

    (UMR7126 Epigenetics and Cell Fate)

  • Yulianna Koziy

    (UMR7126 Epigenetics and Cell Fate)

  • Souhila Medjkane

    (UMR7126 Epigenetics and Cell Fate)

  • Sergio Valente

    (Sapienza University of Rome)

  • Rossella Fioravanti

    (Sapienza University of Rome)

  • Catherine Pioche-Durieu

    (CNRS, UMR 7592 Institut Jacques Monod)

  • Laurent Lignière

    (CNRS, UMR 7592 Institut Jacques Monod)

  • Guillaume Chevreux

    (CNRS, UMR 7592 Institut Jacques Monod)

  • Antonello Mai

    (Sapienza University of Rome
    Sapienza University of Rome)

  • Jonathan B. Weitzman

    (UMR7126 Epigenetics and Cell Fate)

Abstract

Intracellular pathogens develop elaborate mechanisms to survive within the hostile environments of host cells. Theileria parasites infect bovine leukocytes and cause devastating diseases in cattle in developing countries. Theileria spp. have evolved sophisticated strategies to hijack host leukocytes, inducing proliferative and invasive phenotypes characteristic of cell transformation. Intracellular Theileria parasites secrete proteins into the host cell and recruit host proteins to induce oncogenic signaling for parasite survival. It is unknown how Theileria parasites evade host cell defense mechanisms, such as autophagy, to survive within host cells. Here, we show that Theileria annulata parasites sequester the host eIF5A protein to their surface to escape elimination by autophagic processes. We identified a small-molecule compound that reduces parasite load by inducing autophagic flux in host leukocytes, thereby uncoupling Theileria parasite survival from host cell survival. We took a chemical genetics approach to show that this compound induced host autophagy mechanisms and the formation of autophagic structures via AMPK activation and the release of the host protein eIF5A which is sequestered at the parasite surface. The sequestration of host eIF5A to the parasite surface offers a strategy to escape elimination by autophagic mechanisms. These results show how intracellular pathogens can avoid host defense mechanisms and identify a new anti-Theileria drug that induces autophagy to target parasite removal.

Suggested Citation

  • Marie Villares & Nelly Lourenço & Ivan Ktorza & Jérémy Berthelet & Aristeidis Panagiotou & Aurélie Richard & Angélique Amo & Yulianna Koziy & Souhila Medjkane & Sergio Valente & Rossella Fioravanti & , 2024. "Theileria parasites sequester host eIF5A to escape elimination by host-mediated autophagy," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45022-7
    DOI: 10.1038/s41467-024-45022-7
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    References listed on IDEAS

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    1. Kevin Cheeseman & Guillaume Jannot & Nelly Lourenço & Marie Villares & Jérémy Berthelet & Teresa Calegari-Silva & Juliette Hamroune & Franck Letourneur & Fernando Rodrigues-Lima & Jonathan B. Weitzman, 2021. "Dynamic methylation of histone H3K18 in differentiating Theileria parasites," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Gennaro Napolitano & Alessandra Esposito & Heejun Choi & Maria Matarese & Valerio Benedetti & Chiara Di Malta & Jlenia Monfregola & Diego Luis Medina & Jennifer Lippincott-Schwartz & Andrea Ballabio, 2018. "mTOR-dependent phosphorylation controls TFEB nuclear export," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    3. J. Marsolier & M. Perichon & J. D. DeBarry & B. O. Villoutreix & J. Chluba & T. Lopez & C. Garrido & X. Z. Zhou & K. P. Lu & L. Fritsch & S. Ait-Si-Ali & M. Mhadhbi & S. Medjkane & J. B. Weitzman, 2015. "Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation," Nature, Nature, vol. 520(7547), pages 378-382, April.
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