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

Marie Villares, Nelly Lourenço, Ivan Ktorza, Jérémy Berthelet, Aristeidis Panagiotou, Aurélie Richard, Angélique Amo, Yulianna Koziy, Souhila Medjkane, Sergio Valente, Rossella Fioravanti, Catherine Pioche-Durieu, Laurent Lignière, Guillaume Chevreux, Antonello Mai and Jonathan B. Weitzman ()
Additional contact information
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
Jonathan B. Weitzman: UMR7126 Epigenetics and Cell Fate

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45022-7

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