Diet-mediated immunometabolic regulation promotes Klebisella pneumoniae airway clearance 2722

Description Antimicrobial-resistant and susceptible Klebsiella pneumoniae (Kp) are major causes of pneumonia and mortality in healthcare settings. One emerging immune evasion strategy of Kp involves its manipulation of the host metabolism, particularly through the induction of mitochondrial oxidative phosphorylation (OXPHOS), which generates reactive oxygen species (ROS). This promotes the accumulation of immunosuppressive myeloid cells that fail to clear bacteria. We hypothesized that reducing ROS with a ketogenic diet would limit anti-inflammatory cells and enhance bacterial clearance. In addition, we postulate that diet-induced ketones would improve immune cell bioenergetics and function. Using a mouse pneumonia model in both BL/6 and Nrf2-/- backgrounds, we compared bacterial burden in mice fed either a ketogenic or control diet. We show that BL/6, but not Nrf2-/- mice lacking antioxidative regulation, which were fed a ketogenic diet had reduced pulmonary bacterial burden and increased survival. These mice had elevated ketones in the blood and airway, along with decreased levels of metabolites associated with myeloid-derived suppressor cells. We observed increased monocytes, neutrophils, and T cells in the lungs of these mice, along with enhanced protein synthesis. Our data highlight the role of ketones in enhancing the immune response to Kp via Nrf2 activation and supporting bioenergetics, suggesting that regulating the host metabolism may help clear persistent infections. Funding Sources This abstract is funded by NIH R00HL157550 (NHLBI). Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)