Project summary/abstract Carbapenem-resistant Klebsiella pneumoniae (Kp) strains belonging to sequence type (ST) 258 have spread globally in the past decades. Their association with often-fatal ventilator-associated pneumonia is of urgent public health concern especially in light of the current COVID-19 pandemic. While numerous studies have focused on investigating antimicrobial resistance strategies, there is still a lack of effective therapeutic agents, which urges the need to better understand other factors that are crucial for Kp ST258 persistence. Kp ST258 strains differ from hypervirulent strains that induce rapidly fatal infections by instead causing subacute chronic infections. Failure to clear Kp ST258 is associated with the recruitment of monocytes (myeloid-derived suppressor cells, MDSCs) with anti-inflammatory properties similar to those that promote the growth of tumor cells during oncogenesis. Given that metabolic activities govern the function of immune cells, we hypothesize that Kp ST258 metabolism in a manner similar to tumor metabolism generates host metabolic stress and a milieu conducive to the generation and expansion of immunosuppressive cells. We found that Kp ST258 stimulates a unique host metabolic response during pulmonary infection that is characterized by the rapid depletion of glucose, stimulation of glutaminolysis and fatty acid oxidation (FAO) pathways that fuel oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS) production, and the accumulation of the antioxidative metabolite itaconate. This project offers a novel approach to develop therapeutic strategies drawing upon the host metabolic response to Kp ST258 as the main factor promoting chronic pulmonary infection. Specifically, aim 1 explores the dynamics of the host immunometabolic response to Kp ST258. Aim 2 seeks to investigate how this response promotes immunosuppression while aim 3 focuses on its direct effect on bacterial adaptation to and survival in the airway by driving global changes in bacterial gene expression including the upregulation of the Type Six Secretion System (T6SS) to counteract oxidative stress.