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Identification of new pseudomonas aeruginosa genes involved in the pathophysiology of cystic fibrosis lung infection


Pseudomonas aeruginosa lung infection is the major cause of morbidity and mortality in Cystic Fibrosis (CF) patients. During chronic colonisation the persisting pathogen adapts to the CF niche due to the disease-specific environmental conditions of the hos t, such as anaerobic mucus layer and the pressure of innate immune defence system. Under those conditions P. aeruginosa evolves specific virulence mechanisms to evade the host defence and increases its fitness/survival. P. aeruginosa acquires adaptive muta tions becoming mucoid, resistant to antibiotics and may carry many others characters, which distinguish the late isolates strains from the initial colonising bacterium. Currently the onset of bacterial colonisation and changes in different phases of infect ion (from acute to chronic) are not completely understood. Although the process of bacterial airway colonisation has been investigated, its impact is restricted to a part of P. aeruginosa strains and insufficient to explain the pathogenicity. Here, we prop ose to use a signature-tagged transposen mutagenesis together with an analysis of P. aeruginosa genome sequence and differential gene expression to identify and characterise new genes involved in the chronic lung infection. A library of P. aeruginosa mutan ts will be constructed by random transposen insertional mutagenesis system and accomplished by tagging each mutant with a unique short DNA sequence so that it can subsequently be identified within a pool of mutants by DNA-DNA hybridization analysis. When a pplied to a chronic murine infection model for CF, mutants with an increased fitness/survival will be recovered from the lung after one week of infection and revealed by identification of the tags. The genomic DNA sequence flanking the transposen will allo w us to assign fimctions to inactivated genes and DNA array technology allow to characterise interaction with other genes. Further investigation on these candidate genes will be carried out #

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