ALGINATE GENE REGULATION AND INFECTION IN INFECTION IN C

铜绿假单胞菌引起严重和衰弱的肺部疾病

Pseudomonas aeruginosa causes severe and debilitating pulmonary infections in children and young adults afflicted with cystic fibrosis (CF). P. aeruginosa isolated from the respiratory tract of CF patients switches from a non-mucoid form to a mucoid, alginate producing form upon progression of the disease. Alginate encapsulation is believed to protect the infecting cells from phagocytosis as well as from antibiotic therapy. Inhibition of the synthesis of this protective alginate barrier may render P. aeruginosa more susceptible to antibiotic therapy and the host immune system, thereby alleviating the complications that arise from P. aeruginosa infections in cystic fibrosis patients. It has been demonstrated that alginate synthesis is triggered by the unique environment in the lungs of CF patients which includes high electrolyte concentrations and a dehydrated mucus. It has been shown that two important genes involved in alginate synthesis, algC and algD, are under the common control of regulatory proteins AlgR1 and AlgR2, which belong to the two-component bacterial signal transduction family. The proposed research is aimed at elucidating the regulatory mechanisms that control the expression of alginate biosynthesis genes. Specifically, the role of AlgR1 in regulation of algC and algD promoters and the detailed mechanisms of phosphorylation will be studied. Furthermore, how environmental signals unique to CF-afflicted lungs are transduced to AlgR2 for its autophosphorylation will be investigated. Understanding various steps in alginate gene activation may allow development of non- toxic inhibitors for this process, and may lead to an effective treatment regimen for the eradication of P. aeruginosa from the CF lung.