Abstract Successful host defense against bacterial pneumonia requires a highly regulated balance between the activation of sufficient inflammation and oxidants to kill inhaled pathogens and an anti-inflammatory and anti- oxidant response to protect the host from tissue damage. The ESKAPE pathogens including S. aureus, K. pneumoniae and P. aeruginosa are multiply antibiotic resistant bacteria associated with substantial morbidity and mortality in hospitalized patients as the cause of pneumonia and sepsis. These bacteria share a remarkable ability to alter their own metabolism and that of the host to limit phagocytic clearance and enable persistent infection. These pathogens robustly stimulate itaconate and fumarate production, among the most abundant metabolites in the infected airway, both with many anti-inflammatory and anti-oxidant consequences. We will test the central hypothesis that itaconate and fumarate function in the orchestration of an effective immune response to these airway pathogens, limiting host damage but at the expense of enabling persistent infection. We will establish how itaconate is linked to the activation of the major anti-oxidant transcription factors, Nrf2, Atf3 and their downstream effectors that may interfere with the clearance of S. aureus and P. aeruginosa by limiting the oxidant tone in the infected airways, important for bacterial killing. We will establish how itaconate and fumarate skew immune cell phenotypes, promoting the anti-inflammatory M2-like macrophage and myeloid derived suppressor cell dominated responses. Both itaconate and fumarate are actively involved in the post translational modification of host and pathogen targets. We will establish how itaconation and succination of bacterial proteins such as the carbon catabolite repressors enhances the ability of these pathogens to persist in the infected lung. Our overarching goal is to establish how immunometabolites contribute to the pathogenesis of persistent airway infection, how different organisms may activate distinctive responses, and to identify targets to enhance our ability to prevent and treat health care associated pneumonias.