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Background   Pseudomonas aeruginosa  ( PA ) is an opportunistic Gram-negative bacterium that causes serious life threatening and nosocomial infections including pneumonia.  PA  has the ability to alter host genome to facilitate its invasion, thus increasing the virulence of the organism. Sphingosine-1- phosphate (S1P), a bioactive lipid, is known to play a key role in facilitating infection. Sphingosine kinases (SPHK) 1&2 phosphorylate sphingosine to generate S1P in mammalian cells. We reported earlier that  Sphk2   −/−   mice offered significant protection against lung inflammation, compared to wild type (WT) animals. Therefore, we profiled the differential expression of genes between the protected group of  Sphk2   −/−   and the wild type controls to better understand the underlying protective mechanisms related to the  Sphk2  deletion in lung inflammatory injury. Whole transcriptome shotgun sequencing (RNA-Seq) was performed on mouse lung tissue using NextSeq 500 sequencing system.    Results  Two-way analysis of variance (ANOVA) analysis was performed and differentially expressed genes following  PA  infection were identified using whole transcriptome of  Sphk2   −/−   mice and their WT counterparts. Pathway (PW) enrichment analyses of the RNA seq data identified several signaling pathways that are likely to play a crucial role in pneumonia caused by  PA  such as those involved in: 1. Immune response to  PA  infection and NF-κB signal transduction; 2. PKC signal transduction; 3. Impact on epigenetic regulation; 4. Epithelial sodium channel pathway; 5. Mucin expression; and 6. Bacterial infection related pathways.  Our genomic data suggests a potential role for SPHK2 in  PA -induced pneumonia through elevated expression of inflammatory genes in lung tissue. Further, validation by RT-PCR on 10 differentially expressed genes showed 100% concordance in terms of vectoral changes as well as significant fold change.    Conclusion  Using  Sphk2   −/−   mice and differential gene expression analysis, we have shown here that S1P/SPHK2 signaling could play a key role in promoting  PA  pneumonia. The identified genes promote inflammation and suppress others that naturally inhibit inflammation and host defense. Thus, targeting SPHK2/S1P signaling in  PA -induced lung inflammation could serve as a potential therapy to combat  PA -induced pneumonia.

bmc genomics

Genetic deletion of Sphk2 confers protection against Pseudomonas aeruginosa mediated differential expression of genes related to virulent infection and inflammation in mouse lung