ROLE OF A NEW SIGNAL MOLECULE IN P. AERUGINOSA VIRULENCE

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Pseudomonas aeruginosa is the most prevalent Gram negative bacteria found in patient with hospital-acquired infections and produces a high mortality rate in both immunocompromised and cystic fibrosis patients. This opportunistic pathogen produces an arsenal of virulence factors, some of which are controlled by the cell density monitoring mechanism as quorum sensing. Quorum sensing involves a signal molecule, the autoinducer, that builds in concentration with bacterial density until a threshold concentration is reached where it binds and activates a transcriptional activator protein. P. aeruginosa uses two quorum sensing systems, las and rhl, to control numerous virulence factors (including LasB elastase) through two primary autoinducers, 3-oxo-C12-HSL and C4-HSL. Recently a third inducer molecule designated as the Pseudomonas Quinolone Signal (PQS) was discovered. Preliminary results show that PQS is regulated by the las quorum sensing system and that it requires at least Rh1R to inducer lasB. To elucidate the PQS synthetic pathway, g3enes characterize factors controlling PQS expression. To elucidate pathway, genes responsible for anthranilate (a PQS precursor) synthesis will be studied, and a phenotypic, and a phenotypic screen based on LasB production will be used to clone other genes responsible for PQS production. To define the role of PQS in P. aeruginosa virulence, reporter gene fusions will be used to determine how PQS affects the expression of different virulence genes. Finally, to study PQS expression, or PQS bioassay will be used to monitor its production under various conditions. The long term goal of this proposal is to determine the role of PQS in the pathogenesis of P. aeruginosa infections with the hope it will lead to new and effective therapies against aeruginosa.