mTOR-dependent metabolic reprogramming promotes K. pneumoniae airway clearance 3114

Abstract Description Klebsiella pneumoniae (Kp) is a leading cause of healthcare-associated pneumonia and often proves refractory to treatment, even when susceptible to antimicrobials. We previously linked the host metabolic response to Kp infection with a maladaptive immune response. Kp infection induces host oxidative phosphorylation (OXPHOS) and the accumulation of immunosuppressive cells that fail to clear bacteria from the airway. Additionally, Kp infection is associated with the depletion of amino acids such as arginine, glutamine, and leucine, all of which play key roles in cellular metabolism via the activation of the metabolic regulator mTOR. We hypothesized that Kp-induced amino acid depletion impairs mTOR activity, leading to metabolic exhaustion and inefficient immune responses. Using Seahorse extracellular flux assays, we show that macrophages pre-treated with glutamine, arginine, or leucine (but not glycine) upregulate glycolysis and OXPHOS upon infection. Leucine treatment improves Kp clearance from the lungs and enhances host survival. Furthermore, Ido1/2-/- mice, which lack enzymes that catabolize tryptophan (another mTOR activator), also show enhanced bacterial clearance and an altered immune landscape. Our findings highlight the role of mTOR and cellular metabolism in promoting effective immune cell function during Kp infection. Our data suggest that targeting host metabolism could offer a promising alternative or adjunctive approach for treating recalcitrant infections. Funding Sources This abstract is funded by: NIH R00HL157550 (NHLBI) Topic Categories Mucosal and Regional Immunology (MUC)