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Nat Commun. 2017 Nov 1;8(1):1232. doi: 10.1038/s41467-017-01345-2.

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

Author information

1
Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Ave N #500, Seattle, WA, 98109, USA.
2
Department of Biomedical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
3
Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA.
4
Program in Molecular and Cellular Biology, 1959 NE Pacific Street, HSB T-466 University Of Washington Box 357275, Seattle, WA, 98195, USA.
5
Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Ave N #500, Seattle, WA, 98109, USA. alexis.kaushansky@cidresearch.org.
6
Department of Global Health, University of Washington, Harris Hydraulics Laboratory Box 357965, Seattle, WA, 98195-7965, USA. alexis.kaushansky@cidresearch.org.

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.

PMID:
29089541
PMCID:
PMC5663700
DOI:
10.1038/s41467-017-01345-2
[Indexed for MEDLINE]
Free PMC Article

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