Global analysis of the eukaryotic pathways and networks regulated by Salmonella typhimurium in mouse intestinal infection in vivo

Acute enteritis caused by Salmonella is a public health concern. Salmonella infection is also known to increase the risk of inflammatory bowel diseases and cancer. Therefore, it is important to understand how Salmonella works in targeting eukaryotic pathways in intestinal infection. However, the global physiological function of Salmonella typhimurium in intestinal mucosa in vivo is unclear. In this study, a whole genome approach combined with bioinformatics assays was used to investigate the in vivo genetic responses of the mouse colon to Salmonella. We focused on the intestinal responses in the early stage (8 hours) and late stage (4 days) after Salmonella infection.

Our study provides novel genome-wide transcriptional profiling data on the mouse colon mucosa's response to the Salmonella typhimurium infection. Building the pathways and networks of interactions between these genes help us to understand the complex interplay in the mice colon during Salmonella infection, and further provide new insights into the molecular cascade, which is mobilized to combat Salmonella-associated colon infection in vivo.

Of the 28,000 genes represented on the array, our analysis of mRNA expression in mouse colon mucosa showed that a total of 856 genes were expressed differentially at 8 hours post-infection. At 4 days post-infection, a total of 7558 genes were expressed differentially. 23 differentially expressed genes from the microarray data was further examined by real-time PCR. Ingenuity Pathways Analysis identified that the most significant pathway associated with the differentially expressed genes in 8 hours post-infection is oxidative phosphorylation, which targets the mitochondria. At the late stage of infection, a series of pathways associated with immune and inflammatory response, proliferation, and apoptosis were identified, whereas the oxidative phosphorylation was shut off. Histology analysis confirmed the biological role of Salmonella, which induced a physiological state of inflammation and proliferation in the colon mucosa through the regulation of multiple signaling pathways. Most of the metabolism-related pathways were targeted by down-regulated genes, and a general repression process of metabolic pathways was observed. Network analysis supported IFN-γ and TNF-α function as mediators of the immune/inflammatory response for host defense against pathogen.