Stage‐Specific Adaptation of HypermutablePseudomonas aeruginosaIsolates during Chronic Pulmonary Infection in Patients with Cystic Fibrosis

Abstract

Mutator strains may evolve from the initially infecting PA strain and generate numerous variants with a loss of destructive virulence factors, probably because of selection for improved survival in the deteriorated CF lung but at the expense of the ability to live freely.

Chronic pulmonary pseudomonal infection in patients with cystic fibrosis: A model for early phase symbiotic evolution

“…This study confirmed that non-mutator and mutator strains coexist in the respiratory tract for prolonged periods in advanced CF. The study also confirmed that mutator strains tend to be the predominant isolates in end-stage CF disease and show startling loss of virulence associated phenotypic traits, including reduced cytotoxicity, amino acid auxotrophy, and inability to survive in tap water (Hogardt et al, 2007). Therefore, the in situ development of isogenic strains appears to be a general phenomenon with mutations affecting the same set of genes, but the specific coding sequence alterations are independent events in clonally unique strains associated with the individual CF host.…”

“…Longitudinal bacterial culture following patient disease progression suggests that a gradual decrease in bacterial diversity is associated with an increase in patient age and advanced pulmonary disease (Cox et al, 2010). Transmission of CF airway adapted strains, for example, a hyper-mucoid Pa, has never been reported (Aaron et al, 2004(Aaron et al, , 2010Feliziani et al, 2010;Furukawa et al, 2006;Hogardt et al, 2007;Oliver & Mena, 2010).…”

“…Other emerging features associated with the adapting CF Pa are more perplexing and include: i) the evolution of slow-growing auxotrophic strains from initially rapidly-growing prototrophic strains; ii) the rise of mutations in virulence determinants from highly virulent wild-type strains; and iii) the emergence of antibiotic hyper-susceptible strains from antibiotic resistant parental strains (Figures 1 and 2) (Agarwal et al, 2005;Barth et al, 1998;Feary et al, 1969;Haussler et al, 1999;Hoboth et al, 2009;Hogardt et al, 2007;Qin et al, 2012;Starkey et al, 2009;Taylor et al, 1992;Thomas et al, 2000;Yang et al, 2008). Moreover, the prototrophic and auxotrophic isogenic strains together show high density growth both in vitro and in vivo, and display variable growth properties and antimicrobial susceptibilities, irrespective of their specific nutrient requirements (Palmer et al, 2007;Qin et al, 2012).…”

“…Genomic profiling of Pa strains isolated from airway secretions of chronically infected CF patients has suggested these organisms undergo a vigorous clonal selection process with secondary emergence of phenotypically divergent isogenic strains (Figures 1 and 2) (Aaron et al, 2004;Cigana et al, 2011;Ciofu et al, 2010;Smith et al, 2006;Head & Yu, 2004;Hogardt et al, 2007;Huse et al;Oliver & Mena, 2010;Oliver et al, 2002). Strains that arise from a founder clone in the same airway show phenotypic dissociation (2-6 phenotypes per specimen) and carry quorum-sensing lasR mutations, as well as noncytotoxic variants with lesions in T3SS (type three secretion system) ExoS and PopD.…”

“…Strains that arise from a founder clone in the same airway show phenotypic dissociation (2-6 phenotypes per specimen) and carry quorum-sensing lasR mutations, as well as noncytotoxic variants with lesions in T3SS (type three secretion system) ExoS and PopD. Most importantly, the accumulation of lossof-function mutations in DNA mismatch repair genes, such as mutS, mutL, and uvrD, has been recognized for its effect on niche-adapted Pa strains with relaxed DNA replication fidelity, and collectively labeled as ''anti-mutator deficient'' properties (Barth & Pitt, 1995a;Dacheux et al, 2000Dacheux et al, , 2001Feliziani et al, 2010;Furukawa et al, 2006;Heurlier et al, 2005;Hogardt et al, 2007;Irvin et al, 1981;Oberhardt et al, 2010;Rau et al, 2010;Roy-Burman et al, 2001;Smith et al, 2006;Thomas et al, 2000;Vendeville et al, 2005;Zierdt & Schmidt 1964). Recently, terms such as ''cheater cells'' and ''easy riders'' have been used to describe this functional heterogeneity and isogenic interdependency (Xavier et al, 2011).…”