Pseudomonas aeruginosa is an opportunistic pathogen that primarily infects injured, immunodeficient or otherwise compromised patients, especially those with cystic fibrosis. The investigator has recently identified a global regulator of gene expression in P. aeruginosa, designated vfr for virulence factor regulator, which is 67% identical to E. coli cyclic AMP receptor protein, CRP. CRP, when complexed with the effector molecule cAMP, functions either as an activator or repressor of numerous genes including, but not limited to those involved in nutrient assimilation, flagellum synthesis, enterotoxin production and the heat shock response. The investigator has found that Vfr, in P. aeruginosa, directly or indirectly regulated the production of numerous proteins, including the virulence factors exotoxin A, elastase, alkaline protease, non-hemolytic phospholipase C, and perhaps others. Thus, the investigator hypothesizes that Vfr plays a central role in the ability of P. aeruginosa to cause disease. Additionally, the identification of the genes whose expression Vfr regulates and characterization of the mechanism which controls Vfr expression will enhance the understanding of how P. aeruginosa causes disease. The investigator will determine whether Vfr is required for virulence of P. aeruginosa using several animal infection models. The investigator will also identify additional genes, including potential virulence factors, which are regulated by Vfr. For these studies, the investigator will use a powerful DNA-binding/antibody capture/PCR amplification technique and random transposon mutagenesis. The P. aeruginosa effector molecule has not been identified. Therefore, the investigator will identify the effector molecule which is required for Vfr activity. The investigator will also characterize the structure/function relationships of Vfr. The investigator proposes that the information gained from this study could lead to the identification and/or development of novel therapeutic approaches against P. aeruginosa. This knowledge is especially important because of the decreasing utility of antibiotics.
| Kanack, Kristen J; Runyen-Janecky, Laura J; Ferrell, Evan P et al. (2006) Characterization of DNA-binding specificity and analysis of binding sites of the Pseudomonas aeruginosa global regulator, Vfr, a homologue of the Escherichia coli cAMP receptor protein. Microbiology 152:3485-96 |
