Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.
Original languageEnglish (US)
JournalScientific Reports
Volume10
Issue number1
DOIs
StatePublished - Mar 4 2020

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