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Mol Syst Biol. 2018 May 17;14(5):e7998. doi: 10.15252/msb.20177998.

The relative resistance of children to sepsis mortality: from pathways to drug candidates.

Author information

1
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
2
Department of Neuroscience, Sheffield Institute for Translational Neurosciences, University of Sheffield, Sheffield, UK.
3
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
4
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
5
Department of Neuroscience, Sheffield Institute for Translational Neurosciences, University of Sheffield, Sheffield, UK winhide@sheffield.ac.uk lkobzik@hsph.harvard.edu.
6
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA winhide@sheffield.ac.uk lkobzik@hsph.harvard.edu.
7
Department of Pathology, Brigham & Women's Hospital, Boston, MA, USA.

Abstract

Attempts to develop drugs that address sepsis based on leads developed in animal models have failed. We sought to identify leads based on human data by exploiting a natural experiment: the relative resistance of children to mortality from severe infections and sepsis. Using public datasets, we identified key differences in pathway activity (Pathprint) in blood transcriptome profiles of septic adults and children. To find drugs that could promote beneficial (child) pathways or inhibit harmful (adult) ones, we built an in silico pathway drug network (PDN) using expression correlation between drug, disease, and pathway gene signatures across 58,475 microarrays. Specific pathway clusters from children or adults were assessed for correlation with drug-based signatures. Validation by literature curation and by direct testing in an endotoxemia model of murine sepsis of the most correlated drug candidates demonstrated that the Pathprint-PDN methodology is more effective at generating positive drug leads than gene-level methods (e.g., CMap). Pathway-centric Pathprint-PDN is a powerful new way to identify drug candidates for intervention against sepsis and provides direct insight into pathways that may determine survival.

KEYWORDS:

connectivity map; drug discovery; pathways; sepsis

PMID:
29773677
PMCID:
PMC5974511

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