Integrative Transcriptomic Profiling Identifies TNF and IL1B as Candidate Key Early-Response Genes in Macrophages Infected with Smooth Brucella Using a Comprehensive Bioinformatic Approach.

Smooth Brucella are the main pathogenic bacteria that threaten human health and food safety. The early stage of smooth Brucella and macrophage interaction is an important phase, and smooth Brucella species elicit a dramatic transcriptional response in infected macrophages. However, the key transcriptional events are still obscure. This study aimed to identify key candidate response pathways and genes in macrophages infected with smooth Brucella at the early interaction stage. Three gene expression profiles including GSE21117, GSE5202, and GSE8385 were retrieved from the NCBI GEO database, and were integrated using comprehensive bioinformatics methods including gene set enrichment analysis, differentially expressed gene analysis, protein and protein interaction (PPI) network construction, and transcription factor prediction. The results showed that 16 up-regulated and 22 down-regulated pathways were identified, including six up-regulated immune-related pathways. A total of 41 up-regulated and four down-regulated genes were identified, and a PPI network including 31 nodes and 134 edges was constructed based on the interactive information of 45 dysregulated genes. A highly correlated module comprising 19 nodes and 103 edges was identified based on the topological features of the whole PPI network. Seven centrality analyses revealed that Tnf and Il1b were essential genes in the highly correlated module, and that the two essential genes were simultaneously enriched in eight significantly up-regulated pathways (including two immune-related pathways). Bcl3 was predicted as a transcription factor in the highly correlated module, and may play regulatory roles in the transcription of Tnf and Il1b genes. The present study identified Tnf and IL1b as candidate key response genes in infected macrophages at the early stage of smooth Brucella and macrophage interaction, which contributes to a deeper understanding of the early key transcriptional events in macrophages infected with smooth Brucella species.