RNAi screening identifies Trypanosoma brucei stress response protein kinases required for survival in the mouse
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 Tr...
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Published in | Scientific reports Vol. 7; no. 1; pp. 6156 - 10 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
21.07.2017
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-017-06501-8 |