Comparison Between Signal Transduction Pathway Activity in Blood Cells of Sepsis Patients and Laboratory Models.

Abstract

Sepsis represents a serious disease burden that lacks effective treatment. Drug development for sepsis requires laboratory models that adequately represent sepsis patients. Simultaneous Transcriptome-based Activity Profiling of Signal Transduction Pathway (STAP-STP) technology quantitatively infers STP activity from mRNA levels of target genes of the STP-associated transcription factor. Here, we used STAP-STP technology to compare STP activities between sepsis patients and lipopolysaccharide (LPS)-based models. Activity scores of Androgen Receptor (AR), TGFβ, NFκB, JAK-STAT1/2, and JAK-STAT3 STPs were calculated based on publicly available transcriptome data. Peripheral blood mononuclear cells (PBMCs) from patients with Gram-negative sepsis, nor PBMCs stimulated with LPS in vitro, showed altered STP activity. Increased NFκB, JAK-STAT1/2, and JAK-STAT3 STP activity was found in whole blood stimulated with LPS in vitro, and in whole blood obtained after intravenous injection of LPS in humans in vivo; AR and TGFβ STP activity only increased in the in vivo LPS model. These results resembled previously reported STP activity in whole blood of sepsis patients. We provide the first comparison of STP activity between patients with sepsis and laboratory model systems. Results are of use for the refinement of sepsis model systems for rational drug development.