Adaptation of Pseudomonas aeruginosa in virulence and metabolism: requirements for chronic lung infection in cystic fibrosis patients

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Chronic Pseudomonas aeruginosa (PA) pneumonia is the major cause of morbidity and mortality among patients suffering from cystic fibrosis (CF). During transition of PA from free-living bacterium to a pulmonary pathogen, a large set of pathogenicity genes is upregulated to establish CF lung colonization and acute infection. During chronic infection PA variants emerge with virulence-attenuated phenotypes probably due to selection by the inflamed CF lung environment. By a detailed analysis of PA isolates from end-stage CF lung disease we identified substantial changes in the transcriptome and proteome of these PA isolates that probably enable PA to establish life-long persistence in the CF lung and are characteristic for so-called chronic virulence pattern (cVP). These changes affect metabolic pathways and stress-response that may lead to increased fitness and metabolic competitiveness of PA in the hostile and hypoxic environment of CF airways. The selection of metabolic variants of PA with increase in dicarboxylate uptake, components of the tricarbon acid cycle (e.g. isocitrate dehydrogenase), arginine metabolism as well as redox active proteins (azurin, cytochrom C peroxidase) seems to be typical for cVP. Several of these factors were also up-regulated during growth of PA under simulated airway growth conditions (oxygen-restriction, artificial CF sputum medium) underlining their metabolic relevance for PA lung persistence. The major aim of this proposal is to unravel the molecular mechanism of metabolic adaptation of PA and the impact of cVP in CF pneumonia. The characterization of cVP of PA in CF lung disease may lead to a better understanding of the pathogenesis of chronic suppurative infection by PA and will help to develop improved antimicrobial therapies.