A Transcriptomic Appreciation of Childhood Meningococcal and Polymicrobial Sepsis from a Pro-inflammatory and Trajectorial Perspective, a Role for VEGF-A and VEGF-B Modulation?

Abstract

This study investigated the temporal dynamics of childhood sepsis by analyzing gene expression (GE) changes associated with pro-inflammatory processes. Five datasets, including four meningococcal sepsis shock (MSS) datasets (two temporal and two longitudinal) and one polymicrobial sepsis dataset, were selected to track temporal changes in gene expression. Hierarchical clustering revealed three temporal phases: early, intermediate, and late, providing a framework for understanding sepsis progression. Principal Component Analysis (PCA) plots supported the identification of gene expression trajectories. Differential gene analysis highlighted consistent up-regulation of VEGF-A and NFKB1, genes involved in inflammation, across the sepsis datasets. NFKB1 gene expression also showed temporal changes in the MSS datasets. In the post-mortem dataset comparing MSS cases to controls, VEGF-A was up-regulated and VEGF-B down-regulated. Renal tissue exhibited higher VEGF-A expression compared to other tissues. Similar VEGF-A upregulation and VEGF-B downregulation patterns were observed in the cross-sectional MSS datasets and the polymicrobial sepsis dataset. Hexagonal plots confirmed VEGFR-VEGFR2 signaling pathway enrichment in the MSS cross-sectional studies. The polymicrobial sepsis dataset also showed enrichment of the VEGF pathway in septic shock day three and sepsis day three samples compared to controls. These findings provide insights into the dynamic nature of sepsis from a transcriptomic perspective, suggesting potential implications for biomarker development. Future research should focus on larger-scale temporal transcriptomic studies with appropriate control groups and validate the identified gene combination as a potential biomarker panel for sepsis.