Evolutionary Genomics of Niche-Specific Adaptation to the Cystic Fibrosis Lung in Pseudomonas aeruginosa

Abstract

The comparative genomics of the transition of the opportunistic pathogen Pseudomonas aeruginosa from a free-living environmental strain to one that causes chronic infection in the airways of cystic fibrosis (CF) patients remain poorly studied. Chronic infections are thought to originate from colonization by a single strain sampled from a diverse, globally distributed population, followed by adaptive evolution to the novel, stressful conditions of the CF lung. However, we do not know whether certain clades are more likely to form chronic infections than others and we lack a comprehensive view of the suite of genes under positive selection in the CF lung. We analyzed whole genome sequence data from 1000 P. aeruginosa strains with diverse ecological provenances including the CF lung. CF isolates were distributed across the phylogeny, indicating little genetic predisposition for any one clade to cause chronic infection. Isolates from the CF niche experienced stronger positive selection on core genes than those derived from environmental or acute infection sources, consistent with recent adaptation to the lung environment. Genes with the greatest differential positive selection in the CF niche include those involved in core cellular processes like metabolism, energy production, and stress response as well as those linked to patho-adaptive processes like antibiotic resistance, cell wall and membrane modification, quorum sensing, biofilms, mucoidy, motility, and iron homeostasis. Many genes under CF-specific differential positive selection had regulatory functions, consistent with the idea that regulatory mutations play an important role in rapid adaptation to novel environments.

LasR-deficient Pseudomonas aeruginosa variants increase airway epithelial mICAM-1 expression and enhance neutrophilic lung inflammation

“…Loss-of-function lasR mutations can emerge under laboratory conditions [16,56,57] and in human infections [58,59]. They are highly prevalent in chronic CF infections, as previously reported by our group and others [13,15,23,60], and numerous genomic studies of longitudinally collected P. aeruginosa clinical strains indicate that the lasR gene is under strong positive selection, with evidence of convergent evolution and pathoadaptation to the CF host [10,13,14,[61][62][63]. Several studies have reported that loss-of-function lasR mutants have increased fitness in conditions such as low oxygen [64,65], denitrification [66], high cell density [67] and growth on certain amino acids [16,68].…”

Macrolide therapy in Pseudomonas aeruginosa infections causes uL4 ribosomal protein mutations leading to high-level resistance

“…Surprisingly, analyzing P. aeruginosa strain collections from different countries and infection scenarios, several uL4 mutations were identified originating primarily from CF patient samples, but also from bacterial meningitis, bacteremia, urine and ventilator associated respiratory infections. This is well in line with the fact that the uL4 encoding rplD gene is under CF niche specific selection 32 , which could possibly be a result of the extensive macrolide use in this environment 32 . It is not clear why so few uL22 mutants are observed in our strain collection but based on the analysis of uL22 mutations in other strain collections, it seems that they are found less often than the uL4 mutations and exclusively in isolates from CF patients.…”

Experimental Evolution of Interference Competition

“…This result suggests that subtle differences in prophage identity and/or epistatic interactions between selected genetic changes interacted with the pre-existing interference competition arsenal to alter the level of killing and/or to promote fitness of evolving strains in general in the selective environment (See Supplementary Text 1). The source of these elements is most likely the clinically isolated recipient strains or from other clinical strains that were being cultured in the laboratory in experiments for other projects (Schoustra et al, 2012;Dettman et al, 2013;Dettman and Kassen, 2020). In case of the strains from the No recipient treatment, phage particles may have been transmitted via aerosols (Verreault et al, 2010;Harms et al, 2017).…”