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

doi:10.1038/s41598-020-60939-x

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

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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 language	English (US)
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-60939-x
State	Published - Mar 4 2020

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledged KAUST grant number(s): CRG4
Acknowledgements: We are grateful to Dr. Bret A. Hassel for manuscript feedback, and Linda Hamburg for her contributions to the mouse and laboratory work. This work was supported in part by the United States Department of Agriculture, Agricultural Research Service (USDA-ARS) (58-5348-4-013), by the Norman Borlaug Commemorative Research Initiative, an initiative between the Feed the Future program of the U.S. Agency for International Development (USAID) and USDA-ARS (58-5348-2-117 F), by the Department for International Development of the United Kingdom, by the Bill and Melinda Gates Foundation (OPP1078791), and by the National Institute of Allergy and Infectious Diseases (T32 AI007540-14, on Immunity and Infection). This work was also supported by the grant Labex ParaFrap (ANR-11-LABX-0024) and core funding from INSERM and the CNRS awarded to GL and a CRG4 grant (URF/1/2610-01-01) from the Office for Sponsored Research (OSR) in King Abdullah University of Science and Technology (KAUST) award to AP and GL and the faculty baseline fund (BAS/1/1020-01-01) awarded to AP.

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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., & Silva, J. C. (2020). Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation. Scientific Reports, 10(1). https://doi.org/10.1038/s41598-020-60939-x

@article{d8c56e94b3364ee29dd76d6a6b960782,

title = "Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation",

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.",

author = "Kyle Tretina and Malak Haidar and Madsen-Bouterse, {Sally A.} and Takaya Sakura and Sara Mfarrej and Lindsay Fry and Marie Chaussepied and Arnab Pain and Knowles, {Donald P.} and Nene, {Vishvanath M.} and Doron Ginsberg and Daubenberger, {Claudia A.} and Bishop, {Richard P.} and Gordon Langsley and Silva, {Joana C.}",

note = "KAUST Repository Item: Exported on 2020-10-01 Acknowledged KAUST grant number(s): CRG4 Acknowledgements: We are grateful to Dr. Bret A. Hassel for manuscript feedback, and Linda Hamburg for her contributions to the mouse and laboratory work. This work was supported in part by the United States Department of Agriculture, Agricultural Research Service (USDA-ARS) (58-5348-4-013), by the Norman Borlaug Commemorative Research Initiative, an initiative between the Feed the Future program of the U.S. Agency for International Development (USAID) and USDA-ARS (58-5348-2-117 F), by the Department for International Development of the United Kingdom, by the Bill and Melinda Gates Foundation (OPP1078791), and by the National Institute of Allergy and Infectious Diseases (T32 AI007540-14, on Immunity and Infection). This work was also supported by the grant Labex ParaFrap (ANR-11-LABX-0024) and core funding from INSERM and the CNRS awarded to GL and a CRG4 grant (URF/1/2610-01-01) from the Office for Sponsored Research (OSR) in King Abdullah University of Science and Technology (KAUST) award to AP and GL and the faculty baseline fund (BAS/1/1020-01-01) awarded to AP.",

year = "2020",

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doi = "10.1038/s41598-020-60939-x",

language = "English (US)",

volume = "10",

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T1 - Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation

AU - Tretina, Kyle

AU - Haidar, Malak

AU - Madsen-Bouterse, Sally A.

AU - Sakura, Takaya

AU - Mfarrej, Sara

AU - Fry, Lindsay

AU - Chaussepied, Marie

AU - Pain, Arnab

AU - Knowles, Donald P.

AU - Nene, Vishvanath M.

AU - Ginsberg, Doron

AU - Daubenberger, Claudia A.

AU - Bishop, Richard P.

AU - Langsley, Gordon

AU - Silva, Joana C.

N1 - KAUST Repository Item: Exported on 2020-10-01 Acknowledged KAUST grant number(s): CRG4 Acknowledgements: We are grateful to Dr. Bret A. Hassel for manuscript feedback, and Linda Hamburg for her contributions to the mouse and laboratory work. This work was supported in part by the United States Department of Agriculture, Agricultural Research Service (USDA-ARS) (58-5348-4-013), by the Norman Borlaug Commemorative Research Initiative, an initiative between the Feed the Future program of the U.S. Agency for International Development (USAID) and USDA-ARS (58-5348-2-117 F), by the Department for International Development of the United Kingdom, by the Bill and Melinda Gates Foundation (OPP1078791), and by the National Institute of Allergy and Infectious Diseases (T32 AI007540-14, on Immunity and Infection). This work was also supported by the grant Labex ParaFrap (ANR-11-LABX-0024) and core funding from INSERM and the CNRS awarded to GL and a CRG4 grant (URF/1/2610-01-01) from the Office for Sponsored Research (OSR) in King Abdullah University of Science and Technology (KAUST) award to AP and GL and the faculty baseline fund (BAS/1/1020-01-01) awarded to AP.

PY - 2020/3/4

Y1 - 2020/3/4

N2 - 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.

AB - 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.

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U2 - 10.1038/s41598-020-60939-x

DO - 10.1038/s41598-020-60939-x

M3 - Article

C2 - 32132598

SN - 2045-2322

VL - 10

JO - Scientific Reports

JF - Scientific Reports

IS - 1

ER -

Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation

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