Hwang, Wontae, Yong, Ji Hyun, Min, Kyung Bae, Lee, Kang-Mu, Pascoe, Ben, Sheppard, Samuel K, and Yoon, Sang Sun
Pseudomonas aeruginosa (PA) is an opportunistic pathogen that causes diverse human infections including chronic airway infection in patients with cystic fibrosis (CF). Comparing the genomes of CF and non-CF PA isolates has great potential to identify the genetic basis of pathogenicity. To gain a deeper understanding of PA adaptation in CF airways, we performed a genome-wide association study (GWAS) on 1,001 PA genomes. Genetic variations identified among CF isolates were categorized into (i) alterations in protein-coding regions, either large- or small-scale, and (ii) polymorphic variation in intergenic regions. We introduced each CF-associated genetic alteration into the genome of PAO1, a prototype PA strain, and validated the outcomes experimentally. Loci readily mutated among CF isolates included genes encoding a probable sulfatase, a probable TonB-dependent receptor (PA2332~PA2336), L-cystine transporter (YecS, PA0313), and a probable transcriptional regulator (PA5438). A promoter region of a heme/hemoglobin uptake outer membrane receptor (PhuR, PA4710) was also different between the CF and non-CF isolate groups. Our analysis highlights ways in which the PA genome evolves to survive and persist within the context of chronic CF infection. Author summary: Understanding how human pathogens, such as Pseudomonas aeruginosa (PA), adapt to the host environment during prolonged infections can provide important information for the treatment of disease. In this study, we compared the genome sequences of PA isolates from cystic fibrosis (CF) and non-CF patients and identified genetic variation that was significantly associated with CF disease. CF-associated genetic variations included: (i) the deletion of three amino acids in a transcriptional regulator (PA5438), which leads to decreased antibiotic susceptibility, enhanced virulence expression and sustained biofilm production in the presence of transferrin, and (ii) the insertion of three amino acids in a cystine transporter (PA0313), which results in decreased pyochelin production. Furthermore, single nucleotide replacement in a promoter was identified and shown to upregulate the cellular process for iron acquisition. Our bioinformatics analyses, linked with experimental validation via genetic manipulation and phenotypic investigation of mutants, provides novel insights into the genomic plasticity of PA during chronic CF infection. [ABSTRACT FROM AUTHOR]