Study Finds That Pseudomonas Aeruginosa’s Ability to Adapt in CF Exacerbates Pulmonary Inflammation

A new study revealed that adaptive changes in Pseudomonas aeruginosa may exacerbate pulmonary inflammation and contribute to the pathogenesis and progression of chronic lung disease in the context of cystic fibrosis. The study entitled “Cystic fibrosis–adapted Pseudomonas aeruginosa quorum sensing lasR mutants cause hyperinflammatory responses” was published in July in the Science Advances journal.

In cystic fibrosis (CF), progressive lung disease is the main cause of symptoms and premature death. The majority of cystic fibrosis patients are chronically infected with the opportunistic pathogen Pseudomonas aeruginosa and have intense neutrophil-associated inflammatory responses that cause lung damage. Since the host immune responses are not effective in eliminating these bacteria, there is persistent bacteria-host interactions, leading to inflammation and immunopathology during CF chronic P. aeruginosa infections.

During P. aeruginosa-host interactions, the bacteria genetically adapts to the CF lung milieu. It has been shown that P. aeruginosa isolates are genotypically and phenotypically different from early-stage and environment-based infections. Chronic infection isolates show adaptive changes, such as conversion to mucoidy or loss of motility, reduced expression of acute virulence factors, such as pilus, extracellular toxins, and enzymes that cause invasive disease.

P. aeruginosa has a transcriptional factor lasR, one of the most important quorum sensing regulators that controls the expression of several exoproducts and acute virulence factors. Quorum sensing is a bacterial communication system that enables microorganisms to synchronize the expression of genes involved in pathogenesis and social microbial behavior in a cell density-dependent manner. Notably, it has been shown that at least a third of chronically infected CF patients have loss-of-function lasR mutants, and this is linked to poorer lung function.

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In this study, the authors evaluated the impact of P. aeruginosa lasR mutants on inflammatory responses in vitro, in vivo and in CF patients. They found that lasR mutants induced an exacerbated neutrophil-predominant inflammatory response. Their findings suggest a mechanism by which P. aeruginosa lasR variants from chronic CF infections augment the inflammation of CF lung and potentially increase disease development.

Importantly, the authors highlight that their findings challenge the current development of inhibitors for P. aeruginosa lasR quorum sensing or bacterial proteases, since this strategy can potentially exacerbate inflammation and pathogenesis during CF.