(526) Pulmonary ketogenesis promotes tolerance to P. aeruginosa infection in the CF lung

Background: P. aeruginosa is a major opportunist that causes chronic respiratory infection in patients with CF. P. aeruginosa readily adapts to the CF lung to coexist with its host, establishing a favorable airway microenvironment that tolerates the pathogen burden. However, exactly how P. aeruginosa promotes this milieu remains poorly understood. Ketone bodies are typically liver metabolites that promote tissue homeostasis not only by fueling cellular bioenergetics, but also by desensitizing phagocytes to infection. Here, we established that P. aeruginosa exploits host ketogenesis to generate an airway milieu that tolerates infection in the CF lung.

Methods: In a murine model of pneumonia, we studied tolerance to a collection of 17 CF host-adapted P. aeruginosa isolates and P. aeruginosa PAO1 as control. Airway and systemic ketones were quantified by metabolomics. The ketogenic program of each lung cell during P. aeruginosa pneumonia was analyzed by single-cell RNA-Seq. Airway accumulation of cytokines and effector cells were examined by ELISA and multi-color flow cytometry, respectively. To establish a ketogenic environment in the lung, we fed animals a fatty acid-rich, carbohydrate low ketogenic diet in comparison to a fatty acid-low, carbohydrate rich control diet.

Results: Both the CF host-adapted P. aeruginosa isolates and PAO1 triggered airway accumulation of ketone bodies during pneumonia. The ketones induced by the CF host-adapted P. aeruginosa isolates were derived from alveolar macrophages, whereas those associated with acute PAO1 infection were produced by the liver. We confirmed the presence of ketone bodies in airway fluids from CF subjects. We recapitulated this ketone-rich environment by feeding mice a ketogenic diet, and found that the CF host-adapted P. aeruginosa isolates exploited this milieu to suppress the inflammatory response to infection. Interestingly, we observed opposite effects with PAO1, which generated more inflammation in ketogenic animals, indicating a distinctive host metabolic response against infection by CF P. aeruginosa isolates.

Conclusions: Our findings demonstrated that CF host-adapted P. aeruginosa isolates co-opted metabolic routes associated with preservation of airway bioenergetic function to trigger tolerance to disease, such as ketone bodies.

Acknowledgements: SAR is funded by CFF RIQUEL21I0. AP is funded by 5R35HL135800.

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