Canonical pathoadaptive cystic fibrosis genes in Pseudomonas aeruginosa are not CF-specific

Abstract

Research on Pseudomonas aeruginosa adaptation in cystic fibrosis (CF) has historically relied on comparing chronic isolates to laboratory reference strains, or evolving reference strains in environments simulating chronic CF. This work has established a small set of genes, including lasR, mucA, and mexZ, as canonical markers of CF patho-adaptation. However, without broad non-CF comparators, it remains unclear how specific these signatures are to CF. We used a structured literature review to define 20 historically emphasized "canonical CF genes", then evaluated their mutational patterns across 4,475 genetically distinct P. aeruginosa genomes from seven defined clinical and environmental contexts. We tested four competing hypotheses: (1) enrichment in adult CF alone, (2) in adult and pediatric CF combined, (3) in chronic lung infections broadly (including non-CF bronchiectasis), or (4) no strong environment-specific enrichment. We found little evidence that canonical gene mutations were specifically enriched in adult CF or CF more broadly. Instead, loss-of-function and individual mutations in genes including mucA, mexB, and mexZ were enriched across chronic lung infections, while most canonical genes (including lasR) showed no strong environment-specific enrichment. These results demonstrate that a canon of genes believed to drive patho-adaptation in CF instead largely reflects the narrow comparative framework of past studies rather than CF-exclusive selection. Our findings emphasize shared evolutionary pressures between CF and non-CF bronchiectasis, highlighting opportunities to exchange research and therapeutic insights across chronic infection clinical contexts.