Identifying host regulators and inhibitors of liver stage malaria infection using kinase activity profiles

Nadia Arang, Heather S. Kain, Elizabeth K. Glennon, Thomas Bello, Denali R. Dudgeon, Emily N. F. Walter, Taranjit S. Gujral and Alexis Kaushansky ()
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Nadia Arang: formerly Seattle Biomedical Research Institute
Heather S. Kain: formerly Seattle Biomedical Research Institute
Elizabeth K. Glennon: formerly Seattle Biomedical Research Institute
Thomas Bello: Fred Hutchinson Cancer Research Center
Denali R. Dudgeon: formerly Seattle Biomedical Research Institute
Emily N. F. Walter: formerly Seattle Biomedical Research Institute
Taranjit S. Gujral: Fred Hutchinson Cancer Research Center
Alexis Kaushansky: formerly Seattle Biomedical Research Institute

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: Abstract Plasmodium parasites have extensive needs from their host hepatocytes during the obligate liver stage of infection, yet there remains sparse knowledge of specific host regulators. Here we assess 34 host-targeted kinase inhibitors for their capacity to eliminate Plasmodium yoelii-infected hepatocytes. Using pre-existing activity profiles of each inhibitor, we generate a predictive computational model that identifies host kinases, which facilitate Plasmodium yoelii liver stage infection. We predict 47 kinases, including novel and previously described kinases that impact infection. The impact of a subset of kinases is experimentally validated, including Receptor Tyrosine Kinases, members of the MAP Kinase cascade, and WEE1. Our approach also predicts host-targeted kinase inhibitors of infection, including compounds already used in humans. Three of these compounds, VX-680, Roscovitine and Sunitinib, each eliminate >85% of infection. Our approach is well-suited to uncover key host determinants of infection in difficult model systems, including field-isolated parasites and/or emerging pathogens.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01345-2

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DOI: 10.1038/s41467-017-01345-2

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