A Transcriptomic Appreciation of Childhood Meningococcal and Polymicrobial Sepsis from a Pro-Inflammatory and Trajectorial Perspective, a Role for Vascular Endothelial Growth Factor A and B Modulation?

Rashid, Asrar; Brusletto, Berit S.; Al-Obeidat, Feras; Toufiq, Mohammed; Benakatti, Govind; Brierley, Joe; Malik, Zainab A.; Hussain, Zain; Alkhazaimi, Hoda; Sharief, Javed; Kadwa, Raziya; Sarpal, Amrita; Chaussabel, Damien; Malik, Rayaz A.; Quraishi, Nasir; Khilnani, Praveen; Zaki, Syed A.; Nadeem, Rashid; Shaikh, Guftar; Al-Dubai, Ahmed; Hafez, Wael; Hussain, Amir

Abstract

This study investigated the temporal dynamics of childhood sepsis by analyzing gene expression changes associated with proinflammatory 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 supported the identification of gene expression trajectories. Differential gene analysis highlighted consistent upregulation of vascular endothelial growth factor A (VEGF-A) and nuclear factor κB1 (NFKB1), genes involved in inflammation, across the sepsis datasets. NFKB1 gene expression also showed temporal changes in the MSS datasets. In the postmortem dataset comparing MSS cases to controls, VEGF-A was upregulated and VEGF-B downregulated. Renal tissue exhibited higher VEGF-A expression compared with 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 VEGF-R (VEGF receptor)–VEGF-R2 signaling pathway enrichment in the MSS cross-sectional studies. The polymicrobial sepsis dataset also showed enrichment of the VEGF pathway in septic shock day 3 and sepsis day 3 samples compared with controls. These findings provide unique insights into the dynamic nature of sepsis from a transcriptomic perspective and suggest 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.

• Journal Article Type: Article
• Acceptance Date: Jul 19, 2023
• Online Publication Date: Aug 9, 2023
• Publication Date: 2023-10
• Deposit Date: Jan 24, 2024
• Publicly Available Date: Jan 24, 2024
• Print ISSN: 1073-2322
• Publisher: Lippincott, Williams & Wilkins
• Peer Reviewed: Peer Reviewed
• Volume: 60
• Issue: 4
• Pages: 503-516
• DOI: https://doi.org/10.1097/shk.0000000000002192
• Keywords: Gene expression, proinflammation, sepsis, septic shock, temporal sepsis, VEGF-A, VEGF-B
• Public URL: http://researchrepository.napier.ac.uk/Output/3491923