Evolution and adaptation ofPseudomonas aeruginosain the paranasal sinuses of people with cystic fibrosis

Abstract

People with the genetic disorder cystic fibrosis (CF) harbor lifelong respiratory infections, with morbidity and mortality frequently linked to chronic lung infections dominated by the opportunistically pathogenic bacterium Pseudomonas aeruginosa. During chronic CF lung infections, a single clone of P. aeruginosa can persist for decades and dominate end-stage CF lung disease due to its propensity to adaptively evolve to the respiratory environment, a process termed pathoadaptation. Chronic rhinosinusitis (CRS), chronic inflammation and infection of the sinonasal space, is highly prevalent in CF and the sinuses may serve as the first site in the respiratory tract to become colonized by bacteria that then proceed to seed lung infections. We identified three evolutionary genetic routes by which P. aeruginosa evolves in the sinuses of people with CF, including through the evolution of mutator lineages and proliferative insertion sequences and culminating in early genomic signatures of host-restriction. Our findings raise the question of whether a significant portion of the pathoadaptive phenotypes previously thought to have evolved in response to selective pressures in the CF lungs may have first arisen in the sinuses and underscore the link between sinonasal and lung disease in CF.

IntracellularPseudomonas aeruginosawithin the airway epithelium of Cystic Fibrosis lung tissues

“…We also employed MiPACT (passive CLARITY technique), a recently developed approach which can reveal the 3D spatial distribution of CF microbes in situ and their relationship with their host cells and tissue structures by confocal microscopy (49,50). Recent advances of this technology allowed the study of the biogeography of CF pathogen in sputum or the upper airways with resolution at the species level using multiplexed molecular probes (31,51). Here, MiPACT was applied for the first time to human lung tissues to visualize CF airways, and combined with immunofluorescence, revealed rare events of intracellular bacteria within the airway epithelium.…”

Development of liquid culture media mimicking the conditions of sinuses and lungs in cystic fibrosis and health

“…They found that the sinuses harboured isolates with pathoadaptive characteristics that were previously seen in isolates from sputum and that have been associated with persistence in the CF lung. 11 The continuous cycle of bacterial clearance from lungs and recolonization from sinuses may form an important part of the intermittent colonization stage that precedes chronic lung infection. 12 This proposed route to lung infection was recapitulated in a mouse natural inhalation infection model with P. aeruginosa, where persistence of bacteria in the upper airways was observed over the course of 28 days of infection.…”

“…They found that the sinuses harboured isolates with pathoadaptive characteristics that were previously seen in isolates from sputum and that have been associated with persistence in the CF lung. 11 The continuous cycle of bacterial clearance from lungs and recolonization from sinuses may form an important part of the intermittent colonization stage that precedes chronic lung infection. 12 …”