Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation.

Scientific reports 2020 Mar 04

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Intracellular pathogens have evolved intricate mechanisms to subvert host cell signaling pathways and ensure their own propagation. A lineage of the protozoan parasite genus Theileria infects bovine leukocytes and induces their uncontrolled proliferation causing a leukemia-like disease. Given the importance of E2F transcription factors in mammalian cell cycle regulation, we investigated the role of E2F signaling in Theileria-induced host cell proliferation. Using comparative genomics and surface plasmon resonance, we identified parasite-derived peptides that have the sequence-specific ability to increase E2F signaling by binding E2F negative regulator Retinoblastoma-1 (RB). Using these peptides as a tool to probe host E2F signaling, we show that the disruption of RB complexes ex vivo leads to activation of E2F-driven transcription and increased leukocyte proliferation in an infection-dependent manner. This result is consistent with existing models and, together, they support a critical role of E2F signaling for Theileria-induced host cell proliferation, and its potential direct manipulation by one or more parasite proteins.

Citation

Kyle Tretina, Malak Haidar, Sally A Madsen-Bouterse, Takaya Sakura, Sara Mfarrej, Lindsay Fry, Marie Chaussepied, Arnab Pain, Donald P Knowles, Vishvanath M Nene, Doron Ginsberg, Claudia A Daubenberger, Richard P Bishop, Gordon Langsley, Joana C Silva. Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation. Scientific reports. 2020 Mar 04;10(1):3982