The morbidity and mortality for most cystic fibrosis (CF) patients is caused by Pseudomonas aeruginosa, however its pathogenesis during early stages of infection of children with CF is poorly understood. P. aeruginosa possesses several virulence factors, which contribute to its pathogenesis. A relatively new class of virulence factor is the type Ill cytotoxins, which are delivered into eukaryotic cells upon the direct binding of the bacterium to the eukaryotic cell membrane. These cytotoxins subvert the host innate immune system, allowing establishment of initial foci of infection. This proposal represents a consortium among researchers at the Medical College of Wisconsin, the National Institutes of Health (NHBLI and NCI) and the Wisconsin CF Neonatal Screening Project and will provide insight into the pathogenesis of P. aeruginosa in children with CF. Recent studies have shown that components of the type-Ill apparatus are commonly expressed in adult CF patients who are infected by P. aeruginosa and that sera from children with CF contain antibodies against the type-Ill apparatus and the type III cytotoxin, ExoS. Two hypotheses will be tested: (i) stable colonization of the lung of children with CF requires expression of the type-Ill system of P. aeruginosa and (ii) the immune response to antigens of the type-Ill system is an early and accurate measurement of infection of the lung of children with CF by P. aeruginosa. This proposal will conduct retrospective and prospective longitudinal studies to determine the expression of the type-Ill system of P. aeruginosa in children with CF and to correlate this data with stable infection by P. aeruginosa, clinical outcome, the child's genotype for host modifier genes. There are three specific aims: measure the immune response to the type-Ill system of P. aeruginosa in children with CF; identify type-III antigens and immunogens of P. aeruginosa isolated from children with CF, and characterize the biological and biochemical properties of type-Ill cytotoxins from P. aeruginosa isolates from children with CF and antibodies to type-Ill cytotoxins. Completion of these studies will define the molecular properties of P. aeruginosa during early infections of children with CF and develop strategies to accurately detect P. aeruginosa infections, as well as, provide insight towards the identification of vaccine candidates to delay or prevent infection.
| Maresso, Anthony W; Deng, Qing; Pereckas, Michael S et al. (2007) Pseudomonas aeruginosa ExoS ADP-ribosyltransferase inhibits ERM phosphorylation. Cell Microbiol 9:97-105 |
| Corech, R; Rao, A; Laxova, A et al. (2005) Early immune response to the components of the type III system of Pseudomonas aeruginosa in children with cystic fibrosis. J Clin Microbiol 43:3956-62 |
| Maresso, Anthony W; Baldwin, Michael R; Barbieri, Joseph T (2004) Ezrin/radixin/moesin proteins are high affinity targets for ADP-ribosylation by Pseudomonas aeruginosa ExoS. J Biol Chem 279:38402-8 |
| Sun, Jianjun; Barbieri, Joseph T (2003) Pseudomonas aeruginosa ExoT ADP-ribosylates CT10 regulator of kinase (Crk) proteins. J Biol Chem 278:32794-800 |
| Maresso, Anthony W; Riese, Matthew J; Barbieri, Joseph T (2003) Molecular heterogeneity of a type III cytotoxin, Pseudomonas aeruginosa exoenzyme S. Biochemistry 42:14249-57 |
