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.
Tretina, K., Haidar, M., Madsen-Bouterse, S.A., Sakura, T., Mfarrej, S., Fry, L., Chaussepied, M., Pain, A., Knowles, D.P., Nene, V.M., Ginsberg, D., Daubenberger, C.A., Bishop, R.P., Langsley, G. and Silva, J.C. 2020. Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation. Scientific Reports 10: 3982.