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Content archived on 2024-05-29

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

Final Activity Report Summary - P. AERUGINOSA NEW GE (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 host, 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. Over-expression of alginate by P. aeruginosa leading to the mucoid phenotype and linked to mucABCD mutations is thought to be a key factor in the organisms' persistence in the CF respiratory tract. In the year covered by the ERG, a collection of clinical strains were screened for presence of muc mutations and correlated with CF pathogenesis. A lack of an association between muc genotype and severity of CF lung disease were found.

Muc mutations were observed with similar frequency in strains collected from two groups of CF patients each with a highly discordant course of chronic P. aeruginosa infection, suggesting that carriage of strains with muc mutations is not informative for the clinical manifestations and prognosis of CF disease. However, when the collection of P. aeruginosa strains was screened for hypermutability, hypermutable phenotypes have been repeatedly observed in high proportion of CF infected patients indicating that this mechanism may play a crucial role in the pathogenesis of bacterial lung infection. Hypermutable strains may generate adaptive variants that confer a survival advantage to P. aeruginosa during chronic lung infection. To know which genes are involved in adaptation to lung the screening of a STM-library of P. aeruginosa mutants is currently in progress.