lasR mutant P. aeruginosa in CF

The CF pathogen P. aeruginosa changes through mutation during chronic lung infections. We identified a mutation that occurs early and frequently among children with CF at our local hospital and that may be associated with worse clinical outcomes. This mutation, in the P. aeruginosa gene lasR, leads to dramatic changes in P. aeruginosa cellular physiology, conferring a growth advantage in the nutrient conditions we believe are characteristic of CF secretions. Unfortunately, these physiological changes also decrease killing by several antibiotics of importance to CF.

These findings suggest that the conditions of the CF airway itself may select for this mutation, and that infection with these mutants may hinder the efficacy of antibiotic therapy for CF lung disease.

Characteristic colony morphology identifies lasR mutant P. aeruginosa CF isolates. (A) LB agar-grown colonies of two clonally-related clinical isolates of P. aeruginosa from a single CF patient, one with an inactivating lasR mutation and the other with wild-type lasR, as indicated. The lasR mutant isolated isplays phenotypes characteristic of lasR mutants, including surface iridescent, metallic sheen, whichi s particularly evident in this photograph (yellow arrow). (B) Another pair of LB agar-grown, clonally-related clinical P. aeruginosa isolates in which one isolate has an inactivating lasR mutation that demonstrates colony lysis and flattening (blue arrow). From Hoffman et al., JCF, 2009.

To test these hypotheses, we are conducting a longitudinal study of clinical isolates of P. aeruginosa from a cohort of children with CF enrolled in a large, multicenter study of CF microbiology: The EPIC studies. We will determine the prevalence of lasR mutation in this larger, more heterogeneous cohort of children, as well as clinical features associated with these infections. Our hope is that the presence of this mutation may be useful in directing therapy, suggesting alternative antibiotics or other treatments that would be more effective in people infected with lasR mutant isolates. In addition, we hope to better understand from our work why P. aeruginosa changes and resists killing during chronic lung infections.

References:
D'Argenio DA*; Wu M*; Hoffman LR, Kulasekara HD, Deziel E, Smith EE, Nguyen H, Ernst RK, Larson Freeman TJ, Spencer DH, Brittnacher M, Hayden HS, Selgrade S, Klausen M, Goodlett DR, Burns JL, Ramsey BW, Miller SI. Growth phenotypes of Pseudomonas aeruginosa lasR mutants adapted to the airways of cystic fibrosis patients. Mol Microbiol. 2007. 64(2):512-33.

Hoffman, LR; Kulasekara, HD; Emerson, J; Houston, LS; Burns, JL; Ramsey, BW; and Miller, SI. Pseudomonas aeruginosa lasR mutants are associated with cystic fibrosis lung disease progression. J. Cyst. Fibros. 2009 Jan;8(1):66-70. Epub Oct., 2008.

Hoffman, LR; Richardson, AR; Houston, LS; Kulasekara, HD; Martens-Habbena, W; Klausen, M; Burns, JL; Stahl, DO; Hassett, D; Fang, F; and Miller, SI. Nutrient availability as a mechanism for selection of antibiotic tolerant Pseudomonas aeruginosa within the CF airway. PLoS Pathogens, 2010 Jan 8;6(1):e1000712.