The YfiBNR Signal Transduction Mechanism Reveals Novel Targets for the Evolution of Persistent Pseudomonas aeruginosa in Cystic Fibrosis Airways

• DOI: 10.1371/journal.ppat.1002760
• Publication Date: 2012-06-14T21:30:12Z
• Authors: Jacob G. Malone; Tina Jaeger; Pablo Manfredi; Andreas Dötsch; Andrea Blanka; Raphael Bos; Guy R. Cornelis; Susanne Häussler; Urs Jenal
• Keywords: 0301 basic medicine; 570; Cystic Fibrosis; QH301-705.5; Protein Conformation; Immunoblotting; Polymerase Chain Reaction; 03 medical and health sciences; Bacterial Proteins; Humans; Immunoprecipitation; Pseudomonas Infections; Biology (General); Respiratory Tract Infections; Membrane Proteins; RC581-607; Adaptation, Physiological; 3. Good health; Mutation; Pseudomonas aeruginosa; Mutagenesis, Site-Directed; Immunologic diseases. Allergy; Research Article; Signal Transduction

The genetic adaptation of pathogens in host tissue plays a key role the establishment chronic infections. While whole genome sequencing has opened up analysis changes occurring during long-term infections, identification and characterization adaptive traits is often obscured by lack knowledge underlying molecular processes. Our research addresses Pseudomonas aeruginosa small colony variant (SCV) morphotypes In lungs cystic fibrosis patients, appearance SCVs correlates with prolonged persistence infection poor lung function. Formation P. linked to increased levels second messenger c-di-GMP. previous work identified YfiBNR system as regulator SCV phenotype. effector this tripartite signaling module membrane bound diguanylate cyclase YfiN. Through combination biochemical analyses we first outline mechanistic principles YfiN regulation detail. particular, identify number activating mutations all three components Yfi regulatory system. shown function via tightly controlled competition between allosteric binding sites on proteins; novel mechanism that apparently widespread among periplasmic systems bacteria. We then show infections CF invade population, driving formation vivo. mutational “scars” yfi genes clinical isolates suggests activity both under positive negative selection vivo continuous c-di-GMP network contributes fitness These experiments uncover an important new principle persistence, valid target for anti-infectives directed against