Gram-negative bacteria activate cellular pathways in plaque microenvironment; Systems biology approach

TL;DR

This study explores how Gram-negative bacteria trigger cellular pathways in blood vessel plaques, contributing to atherosclerosis.

Contribution

The paper introduces a systems biology approach to identify activated pathways in different cell types and plaque networks after bacterial exposure.

Findings

Cytokine and INF pathways were significantly activated in endothelial cells due to Gram-negative infections.

Netrin-1 and EGFR pathways were activated in plaque networks, while immune pathways were enriched in atheroma plaques.

Cell cross-talks were found to exacerbate pathway activation in unstable plaques.

Abstract

Inflammatory events followed by bacterial infections are related to the progression of the atherosclerosis process. The study investigated the signaling and metabolic pathways of endothelial cells (ECs), macrophages (MQs), vascular smooth muscle cells (VSMCs), and dendritic cells (DCs) after exposure to Gram-negative bacterial infections. Moreover, it aimed at cross-talking and enriching the pathways on the cellular and plaque networks.

High-throughput expression data series (n = 9) were selected through GEO and MAT data repositories. Upregulated differential expression genes (DEGs) were determined using R software and applied to identify the cellular signaling pathways using Enricher/Reactome tools. Then, the cell networks were visualized using the Cytoscape software and enriched by the pathways of secretory proteins identified using Gene ontology (GO).

The important pathways of the Cytokines (Degree 4, p < 6 × 10–26), and INF (Degree 4, p < 8.6 × 10–31) in ECs, Cytokines (Degree 4, p < 9.35 × 10–8), and GPCR (Degree 3, p < 1.45 × 10–4) in MQs, NOTCH (Degree 6, p < 0.027) in VSMCs, and Cytokines (Degree 4, p < 1.45 × 10–17) in DCs were found to be activated and enriched after exposure to Gram-negative bacterial infections on the cell networks. Furthermore, the Netrin- 1 (Degree 6, p < 0.028), and EGFR (Degree 5, p < 0.036) pathways were activated in the intimal thick/xanthoma plaque network while the innate (Degree 9, p < 8.9 × 10–20) and adaptive (Degree 7, p < 4.1 × 10–12) immune systems pathways were activated in the fibrous cap atheroma plaque network.

The study revealed the signaling pathways after exposure to Gram-negative bacterial infections on the cell networks in the vessel microenvironment. Furthermore, the cell cross-talks exacerbated these pathways in cells and unstable plaques.

Not applicable.

The online version contains supplementary material available at 10.1186/s12866-025-03933-5.

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