GlpR Regulates the Glyoxylate Pathway and Virulence Factor Production by Pseudomonas aeruginosa
Type of Degreedissertation
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Pseudomonas aeruginosa infections are the leading cause of morbidity and mortality for cystic fibrosis (CF) patients. P. aeruginosa establishes life-long infection in the CF lung by utilizing various adaptation strategies to cause a chronic infection including alterations in central metabolic activities. The glyoxylate pathway is utilized by bacteria to grow on acetate or fatty acids as a sole carbon source to replenish intermediates of the tricarboxylic acid cycle and it appears to play a role in P. aeruginosa persistence in the CF lung. Son et. al. (2007) demonstrated that the genes encoding for the glyoxylate pathway enzymes, aceA and glcB which encode for isocitrate lyase (ICL) and malate synthase respectively, are upregulated in P. aeruginosa growing in the CF lung. In addition, we determined that this pathway becomes permanently upregulated in some CF adapted isolates of P. aeruginosa (Hagins et. al. 2010, 2011; Lindsey et. al. 2008). The occurrence of these isolates suggests deregulation of the glyoxylate pathway may benefit P. aeruginosa growing within the CF lung. However, the mechanism(s) responsible for alterations in the pathway have yet to be elucidated. GlpR is a transcriptional repressor that regulates the genes responsible for glycerol metabolism in P. aeruginosa. I demonstrate in this body of work that GlpR also regulates the glyoxylate pathway. To date, regulators of the glyoxylate pathway in P. aeruginosa have not been identified with the exception of RpoN, which plays an indirect role in the regulation of this pathway. GlpR’s role in the regulation of the glyoxylate pathway provides a novel perspective into the interplay between fatty acid and glycerol metabolism in P. aeruginosa. Finally, I show that glycerol metabolism is altered in a CF adapted isolate of P. aeruginosa compared to an acute isolate and that production of alginate is influenced by growth on glycerol. Alginate is an important virulence determinant produced by P. aeruginosa during infection of the CF lung. These results suggest the carbon sources present in the CF infection environment impact virulence factor production by P. aeruginosa.