Pathogenic Mechanism for Lung Infection in Mucoid Pseudomonas

ABSTRACT Many VA patients are susceptible and succumb to infections with the opportunistic pathogen, Pseudomonas aeruginosa. This can occur as a complication of COPD, emphysema, chronic bronchitis, cancer and immunosuppressive drug therapy. Exposure to this ubiquitous bacterium can result in nosocomial infections, which are common via respiratory ventilators, catheters, lumbar punctures and general surgery. P. aeruginosa is highly tolerant or resistant to most antibiotics, making it difficult to control such infections, which leads to a high rate of morbidity/mortality. The goal of this research is to improve our understanding of the biosynthesis and regulation of a protective capsule- like polysaccharide called alginate, which is produced as a virulence factor by P. aeruginosa. During chronic respiratory infections (e.g., COPD), adaptive mutations are observed to occur in vivo that lead to the over production of this exopolysaccharide, which confers a mucoid colony phenotype and resistance to phagocytic killing. This suggests a high selective pressure for alginate production in the lung environment. Most of the enzymes for the production of alginate are clustered in the large algD operon. The mucoid phenotype is usually due to mutations that activate sigma-22. However, we have discovered an alternate pathway for alginate production that involves a 2-component regulator pair (AlgB-KinB) and sigma-54 (RpoN). Also, sigma-38 (RpoN) plays an important role in alginate production, but this is not understood. Improving our understanding of this pathogenic mechanism in P. aeruginosa will enhance the management of pulmonary disease caused by this bacterium. In this study, we will: (1) Determine the role of RpoN (sigma-54) in the control of alginate production, (2) Determine the role of RpoS (sigma-38) in the control of alginate production and (3) Identify drugs that enhance the phagocytosis of mucoid Pseudomonas as potential therapeutic agents. The long-term goal of this research is to better understand alginate production by P. aeruginosa as a critical virulence factor during pulmonary infection. The information gained could be vital for the development of new therapeutic approaches in the treatment of P. aeruginosa infections.