COBRE P2: A NOVEL REGULATOR OF P AERUGINOSA VIRULENCE GENES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Pseudomonas aeruginosa is a common lung pathogen that causes ventilator-associated pneumonia, chronic obstructive pulmonary disease, and lung infections associated with Cystic Fibrosis. P. aeruginosa virulence can be attributed in part to its formation of antibiotic-resistant biofilms and secretion of virulence factors including phospholipase C (PlcH). PlcH degrades phosphatidylcholine (PC), the main component of lung surfactant and the predominant phospholipid in the membranes of host, and PlcH production is associated with epithelial destruction, inflammation, and disease severity. Here, we focus on a transcription factor that we identified, GbdR, that controls the expression of plcH in response to glycine betaine, a PC degradation product. GbdR regulates over one hundred genes and in necessary for a variety of virulence phenotypes including biofilm formation in phosphatidylcholine-rich environments. We hypothesize that GbdR coordinately controls expression of plcH as well as other genes relevant to P. aeruginosa pathogenesis. Our specific aims are (1) to test the hypothesis that a subset of the genes that are differentially expressed in choline and PC-containing media are controlled by GbdR and are involved in processes other than choline catabolism, (2) to identify the GbdR binding site and to test the hypothesis that the GbdR-recognition motif is present in a subset of the GbdR-controlled genes identified in Aim 1, and (3) to test the hypothesis that GbdR-controlled genes participate in biofilm formation and virulence. Knowledge of pathways that contribute to biofilm formation and virulence may provide insight into novel ways to prevent or treat P. aeruginosa in the lung.