Genomic variants distinguish Pseudomonas aeruginosa from cystic fibrosis sputum and bloodstream infection

Pseudomonas aeruginosa is an opportunistic human pathogen that causes a variety of acute and chronic infections in humans. However, the genetic basis of its ability to cause distinct diseases in different body sites remains unclear. We aim to identify the genomic elements that distinguish P. aeruginosa derived from bloodstream infections and sputum from cystic fibrosis (CF). We carried out phylogenetic analysis and genome-wide association study (GWAS) of a P. aeruginosa dataset consisting of 840 genomes derived from CF sputum and 249 genomes from bloodstream infections. We identified 342 distinct sequence types (ST). Ten STs were most prevalent (ST111, ST244, ST235, ST549, ST463, ST233, ST309, ST654, ST253, and ST357) and collectively accounted for 38.7% of the dataset. These ten STs were detected in both bloodstream- and CF sputum-derived genomes, albeit at different proportions. We detected specific antimicrobial resistance and virulence genes that were significantly enriched in bloodstream- or CF sputum-derived genomes. GWAS based on single nucleotide polymorphisms (SNPs) in the core genome, unitigs, and accessory genes revealed genomic variants that differ between the two groups, which are associated with a variety of functions, including stress response, nutrient acquisition, defense and redox activity. Narrow-sense heritability associated with variation in infection site is moderately high for SNPs (h2 = 0.737) and accessory genes (h2 = 0.612), but low for unitig variation (h2 = 0.25). Controlling for population structure, we carried out GWAS on 110 phylogenetically matched genomes, which uncovered additional loci distinguishing bloodstream-derived and CF-derived genomes. Those genes with the most pronounced associations are related to nutrient transport and metabolism (carbohydrate, ethanol, lipid, menaquinone (vitamin K2), phenazine, phosphate), siderophore pyoverdine, peptidoglycan remodeling, and stress response. In conclusion, our study reveals the loci that are enriched in P. aeruginosa derived from CF sputum and from bloodstream infections. The observed genetic associations lie largely on the differential antibiotic selection pressure and the dissimilarity between acute versus chronic isolates. The genomic heterogeneity of P. aeruginosa from distinct diseases underscores its opportunistic lifestyle and ecological versatility, and this knowledge is critical to improving our ability to manage infections and improve patient outcomes.