Location: Animal Disease ResearchTitle: Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation
|TRETINA, KYLE - University Of Maryland School Of Medicine|
|HAIDAR, MALAK - Universite Paris Descartes|
|MADSEN-BOUTERSE, SALLY - Washington State University|
|SAKURA, TAKAYA - Universite Paris Descartes|
|MFARREJ, SARA - King Abdullah University Of Science And Technology|
|CHAUSSEPIED, MARIE - Universite Paris Descartes|
|PAIN, ARNAB - King Abdullah University Of Science And Technology|
|KNOWLES, DONALD - Washington State University|
|NENE, VISHVANATH - International Livestock Research Institute (ILRI) - Kenya|
|GINSBERG, DORON - Weizmann Institite Of Science|
|DAUBENBERGER, CLAUDIA - Swiss Tropical Institute(STI)|
|BISHOP, RICHARD - Washington State University|
|LANGSLEY, GORDON - Universite Paris Descartes|
|SILVA, JOANA - University Of Maryland|
Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/18/2020
Publication Date: 3/4/2020
Citation: Tretina, K., Haidar, M., Madsen-Bouterse, S.A., Sakura, T., Mfarrej, S., Fry, L.M., Chaussepied, M., Pain, A., Knowles, D.P., Nene, V.M., Ginsberg, D., Daubenberger, C.A., Bishop, R.P., Langsley, G., Silva, J.C. 2020. Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation. Scientific Reports. 10. https://doi.org/10.1038/s41598-020-60939-x.
Interpretive Summary: Theileria parva, an intracellular protozoan parasite, is the leading infectious cause of death of cattle in sub-Saharan Africa. Current preventive strategies are incredibly limited, and improved vaccination and treatment strategies are urgently needed to decrease the socioeconomic impact of this parasite. One significant hindrance to the development of a new vaccine or new treatment modalities is the lack of specific antigenic targets within the parasite. This work revealed a new, potential vaccine or therapeutic target in T. parva (TpGcpE), a protein that is responsible for cellular transformation in fatal disease. This finding will enable future work in vaccine and treatment development in this disease.
Technical 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.