Pseudomonas aeruginasa LPS: A Post-Genomic Analysis

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DESCRIPTION (provided by the applicant): The long-term goal of this research is to understand the role of lipopolysaccharide (LPS) in the virulence of Pseudomonas aeruginosa in order to develop novel therapeutics and vaccines to combat this important pathogen. The O antigen portion of P. aeruginosa LPS is required for virulence in acute infections and its loss is critical for chronic lung infections in cystic fibrosis patients. The experiments in the parent grant are directed at defining the pathway of synthesis of the O antigen from the serogroup O11 strain PAl03, determining the transcriptional organization of this O antigen locus, and testing O antigen mutants in two different mouse models of infection. The goal of this exploratory grant is to understand how P. aeruginosa 0 antigen is regulated. One of the conditions that has been shown to dramatically effect the expression of P. aeruginosa 0 antigen is temperature; at 45 degrees C, no O antigen is expressed. We will analyze RNA and protein products to determine whether O antigen is transcriptionally or post-transcriptionally regulated. Using genetic approaches, we will identify the O antigen regulator. We will mutate this temperature regulator and use post-genomic techniques including micro-array and proteomic analyses to identify additional genes and proteins that are regulated with O antigen. Uncovering the nature of this regulation will allow us to propose mechanisms to inhibit O antigen expression and thereby decrease the virulence of this bacterium in acute infections. Results obtained through this grant, in combination with the mutational analysis and virulence studies described in the parent proposal, may be beneficial in the development of new strategies that target this important opportunistic pathogen.