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

Nature Communications
Nadia ArangAlexis Kaushansky

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.

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Citations

Dec 5, 2017·Frontiers in Microbiology·Meghan ZuckAlexis Kaushansky
May 9, 2019·Cell Death and Differentiation·Heather S KainAlexis Kaushansky
Dec 20, 2019·JCI Insight·Iset Medina VeraLiliana Mancio-Silva
Feb 18, 2021·Trends in Parasitology·Jack AdderleyChristian Doerig
Jul 24, 2021·Cell Reports Methods·Thomas BelloTaranjit S Gujral
Jul 2, 2021·Chemical Reviews·Kamalakannan VijayanAlexis Kaushansky
Oct 2, 2021·Proceedings of the National Academy of Sciences of the United States of America·Thomas BelloTaranjit S Gujral

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Methods Mentioned

BETA
fluorescence microscopy
genetic knockdown
ubiquitination
gene knockdown
transfection
PCR

Software Mentioned

DAVID Bioinformatics Resources
MATLAB

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