RNAi screening identifies Trypanosoma brucei stress response protein kinases required for survival in the mouse

Abstract Protein kinases (PKs) are a class of druggable targets in Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (sleeping sickness), yet little is known about which PKs are essential for survival in mammals. A recent kinome-wide RNAi screen with 176 individual bloodstream...

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Autores principales:	Fernando Fernandez-Cortes, Tiago D. Serafim, Jonathan M. Wilkes, Nathaniel G. Jones, Ryan Ritchie, Richard McCulloch, Jeremy C. Mottram
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f42ca3b4269e44a1a0bd4fab4c2527c1
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spelling	oai:doaj.org-article:f42ca3b4269e44a1a0bd4fab4c2527c12021-12-02T12:31:46ZRNAi screening identifies Trypanosoma brucei stress response protein kinases required for survival in the mouse10.1038/s41598-017-06501-82045-2322https://doaj.org/article/f42ca3b4269e44a1a0bd4fab4c2527c12017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06501-8https://doaj.org/toc/2045-2322Abstract Protein kinases (PKs) are a class of druggable targets in Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (sleeping sickness), yet little is known about which PKs are essential for survival in mammals. A recent kinome-wide RNAi screen with 176 individual bloodstream form Trypanosoma brucei lines identified PKs required for proliferation in culture. In order to assess which PKs are also potential virulence factors essential in vivo, lines were pooled, inoculated into mice, and screened for loss of fitness after 48 h RNAi. The presence of trypanosomes in the bloodstream was assessed using RNAi target sequencing (RITseq) and compared to growth in culture. We identified 49 PKs with a significant loss of fitness in vivo in two independent experiments, and a strong correlation between in vitro and in vivo loss of fitness for the majority. Nine PKs had a more pronounced growth defect in vivo, than in vitro. Amongst these PKs were several with putative functions related to stress responses mediated through the PI3K/TOR or MAPK signaling cascades, which act to protect the parasite from complement-mediated and osmotic lysis. Identification of these virulence-associated PKs provides new insights into T. brucei-host interaction and reveals novel potential protein kinase drug targets.Fernando Fernandez-CortesTiago D. SerafimJonathan M. WilkesNathaniel G. JonesRyan RitchieRichard McCullochJeremy C. MottramNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Fernando Fernandez-Cortes Tiago D. Serafim Jonathan M. Wilkes Nathaniel G. Jones Ryan Ritchie Richard McCulloch Jeremy C. Mottram RNAi screening identifies Trypanosoma brucei stress response protein kinases required for survival in the mouse
description	Abstract Protein kinases (PKs) are a class of druggable targets in Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (sleeping sickness), yet little is known about which PKs are essential for survival in mammals. A recent kinome-wide RNAi screen with 176 individual bloodstream form Trypanosoma brucei lines identified PKs required for proliferation in culture. In order to assess which PKs are also potential virulence factors essential in vivo, lines were pooled, inoculated into mice, and screened for loss of fitness after 48 h RNAi. The presence of trypanosomes in the bloodstream was assessed using RNAi target sequencing (RITseq) and compared to growth in culture. We identified 49 PKs with a significant loss of fitness in vivo in two independent experiments, and a strong correlation between in vitro and in vivo loss of fitness for the majority. Nine PKs had a more pronounced growth defect in vivo, than in vitro. Amongst these PKs were several with putative functions related to stress responses mediated through the PI3K/TOR or MAPK signaling cascades, which act to protect the parasite from complement-mediated and osmotic lysis. Identification of these virulence-associated PKs provides new insights into T. brucei-host interaction and reveals novel potential protein kinase drug targets.
format	article
author	Fernando Fernandez-Cortes Tiago D. Serafim Jonathan M. Wilkes Nathaniel G. Jones Ryan Ritchie Richard McCulloch Jeremy C. Mottram
author_facet	Fernando Fernandez-Cortes Tiago D. Serafim Jonathan M. Wilkes Nathaniel G. Jones Ryan Ritchie Richard McCulloch Jeremy C. Mottram
author_sort	Fernando Fernandez-Cortes
title	RNAi screening identifies Trypanosoma brucei stress response protein kinases required for survival in the mouse
title_short	RNAi screening identifies Trypanosoma brucei stress response protein kinases required for survival in the mouse
title_full	RNAi screening identifies Trypanosoma brucei stress response protein kinases required for survival in the mouse
title_fullStr	RNAi screening identifies Trypanosoma brucei stress response protein kinases required for survival in the mouse
title_full_unstemmed	RNAi screening identifies Trypanosoma brucei stress response protein kinases required for survival in the mouse
title_sort	rnai screening identifies trypanosoma brucei stress response protein kinases required for survival in the mouse
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f42ca3b4269e44a1a0bd4fab4c2527c1
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RNAi screening identifies Trypanosoma brucei stress response protein kinases required for survival in the mouse

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