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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.

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