Evolutionary trade-offs associated with pmrB mutations in host-adapted Pseudomonas aeruginosa

Populations of Pseudomonas aeruginosa colonise the upper airway of cystic fibrosis patients, providing a reservoir of host-adapted genotypes that subsequently establish chronic lung infection. We have previously experimentally evolved P. aeruginosa LESB65 in a murine model of chronic respiratory tract infection and observed mutations in pmrB that promoted establishment and persistence of infection. Here we show that mutations in pmrB, which encodes the sensor kinase of the PmrAB two-component regulatory system, are acquired early in infection and result in increased resistance to the host antimicrobial lysozyme but enhanced susceptibility to multiple antibiotics. Proteomic analysis of a ?pmrB deletion mutant revealed downregulation of proteins involved in LPS biosynthesis, antimicrobial resistance and phenazine production, and upregulation of proteins involved in adherence, lysozyme resistance and inhibition of the chloride ion channel CFTR, relative to wild-type LESB65. Accordingly, ?pmrB showed enhanced adherence to airway epithelial cells and induced downregulation of host airway epithelial cell CFTR expression. Mutations in pmrB are found in P. aeruginosa isolates from CF patients and are associated with the same host-adapted phenotypes, but are subject to an evolutionary trade-off: While mutations in pmrB provide enhanced colonisation potential, resistance to host immune defences and the ability to modulate the host environment through CFTR inhibition, they concomitantly increase susceptibility to antibiotics.