Abstract
Pseudomonas aeruginosa is an important agent of acute or chronic airway infections. A complex set of genetic and environmental factors determine outcomes of P. aeruginosa airway infections.
P. aeruginosa undergoes genetic adaptation to finetune expression of a type III secretion system (T3SS) and other virulence factors in response to selective pressures during infection. Genetic and environmental factors predispose for P. aeruginosa infections in patients such as those with cystic fibrosis (CF). CF is a genetic disorder resulting in hypoxia and thick mucus that fosters P. aeruginosa airway infection. Resident alveolar macrophages (AMs) coordinate immune responses to P. aeruginosa by producing proinflammatory cytokines such as IL-1β, which can promote infection resistance. AMs infected with P. aeruginosa laboratory strains detect the T3SS and activate the NLRC4 inflammasome, resulting in IL-1β release. Studies of inflammasome responses in AMs to a P. aeruginosa CF isolate of have not been reported. Here, we characterized the CF isolate DH1137 and found it has a downregulated but functional T3SS, is adapted to grow in hypoxia, and induces significant production of the inflammasome cytokines IL-1α and IL-1β during acute lung infection in a CF mouse model. Inflammasome gene expression was primed in AMs by LPS, and upon DH1137 infection these cells released IL-1β. Infection of AMs with DH1137 or laboratory strain PAO1 in hypoxia resulted in significantly dampened inflammasome activation compared to normoxia. These data describe a new mechanism that P. aeruginosa may exploit to evade immune detection by tissue-resident lung macrophages in the context of CF.
Importance
Airway infection of people with CF by P. aeruginosa results from genetic and environmental changes that impact host and pathogen. Mutations in the cystic fibrosis transmembrane conductance regulator gene ( CFTR ) cause anatomical alterations in airways, including areas of hypoxia, that compromise anti-bacterial defense. P. aeruginosa genetically adapts by downregulating a T3SS important for establishment and turning up phenotypes that promote chronic infection such as hypoxic growth. AMs are resident airway phagocytes that can normally detect P. aeruginosa and undergo inflammasome activation to release IL-1 cytokines, however these cells are known to be dysregulated in CF, and their interactions with clinical isolates are understudied. Here show that P. aeruginosa elicits IL-1 cytokines during acute lung infection in a CF mouse model but triggers low inflammasome activation in hypoxic AMs ex vivo, suggesting the bacterium exploits low oxygen to evade detection by resident lung macrophages in CF.
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