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Updated: Oct 16, 2025
A Data-Driven Approach to Quantifying Immune States in Sepsis
Published on: February 7, 2025
Transcriptomic Profiles in Children With Septic Shock With or Without Immunoparalysis
Andrew Snyder1, Kathleen Jedreski1, James Fitch2
1Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
Insights
Children with septic shock and immunoparalysis show distinct gene expression patterns, offering potential for early diagnosis. This research identifies key immune pathway differences to guide future treatments.
Area of Science:
- Pediatric critical care medicine
- Immunology
- Genomics
Background:
- Severe innate immune suppression, or immunoparalysis, in children with septic shock increases infection and mortality risks.
- Current diagnostic methods for pediatric immunoparalysis are lacking, and underlying mechanisms are not well understood.
- Transcriptomic studies have identified gene expression changes in septic children, but immune function assays and specific profiles for immunoparalysis are largely unexamined.
Purpose of the Study:
- To identify distinct RNA expression patterns in children with septic shock and immunoparalysis compared to those with a normal immune response.
- To explore potential transcriptomic biomarkers for diagnosing immunoparalysis in pediatric septic shock.
- To elucidate the molecular mechanisms underlying immunoparalysis in children.
Main Methods:
- A nested case-control study was conducted involving children with septic shock.
- Blood samples were analyzed using RNA sequencing (RNAseq) to compare gene expression between children with and without immunoparalysis (defined by lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)α response < 200 pg/ml).
- Differential gene expression and pathway analyses were performed using DESeq2 and Ingenuity Pathway Analysis software.
Main Results:
- 2,303 transcripts were differentially expressed between the immunoparalysis and normal response groups (absolute fold change ≥ 1.5, false discovery rate ≤ 0.05).
- Downregulated pathways in immunoparalysis included those crucial for cell-mediated immunity, innate-adaptive immune cell interactions, and natural killer cell signaling.
- Upregulated pathways involved humoral immunity, corticotropin signaling, platelet activation, and leukocyte migration.
Conclusions:
- Gene expression profiling shows promise for identifying children with immunoparalysis.
- Key differentially regulated pathways in innate and adaptive immunity were identified, offering insights into disease pathophysiology.
- Further research aims to dissect immune interactions in septic children to guide personalized immunotherapeutic strategies.
Background:
Severe innate immune suppression, termed immunoparalysis, is associated with increased risks of nosocomial infection and mortality in children with septic shock. Currently, immunoparalysis cannot be clinically diagnosed in children, and mechanisms remain unclear. Transcriptomic studies identify subsets of septic children with downregulation of genes within adaptive immune pathways, but assays of immune function have not been performed as part of these studies, and little is known about transcriptomic profiles of children with immunoparalysis.
Methods:
We performed a nested case-control study to identify differences in RNA expression patterns between children with septic shock with immunoparalysis (defined as lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)α response < 200 pg/ml) vs those with normal LPS-induced TNFα response. Children were enrolled within 48 hours of the onset of septic shock and divided into two groups based on LPS-induced TNFα response. RNA was extracted from whole blood for RNAseq, differential expression analyses using DESeq2 software, and pathway analyses using Ingenuity Pathway Analysis.
Results:
32 children were included in analyses. Comparing those with immunoparalysis (n =19) to those with normal TNFα response (n = 13), 2,303 transcripts were differentially expressed with absolute value fold change ≥ 1.5 and false discovery rate ≤ 0.05. The majority of downregulated pathways in children with immunoparalysis were pathways that involved interactions between innate and adaptive immune cells necessary for cell-mediated immunity, crosstalk between dendritic cells and natural killer cells, and natural killer cell signaling pathways. Upregulated pathways included those involved in humoral immunity (T helper cell type 2), corticotropin signaling, platelet activation (GP6 signaling), and leukocyte migration and extravasation.
Conclusions:
Our study suggests that gene expression data might be useful to identify children with immunoparalysis and identifies several key differentially regulated pathways involved in both innate and adaptive immunity. Our ongoing work in this area aims to dissect interactions between innate and adaptive immunity in septic children and to more fully elucidate patient-specific immunologic pathophysiology to guide individualized immunotherapeutic targets.
