Host immunity in the lung is determined by the enhanced utilization of glucose by multi-drug resistant Klebsiella pneumoniae

PROJECT SUMMARY/ABSTRACT When the airways of children dependent on ventilators become infected with multi-drug resistant (MDR) organisms, such as Klebsiella pneumoniae (KP), their risk of acute deterioration and even death increases. Difficult to eradicate, MDR KP have been identified as a major threat to human respiratory health. Therefore, studying the mechanisms of how the lung is affected by MDR bacteria is very important for this high-risk patient population. One hypothesis for their success is that the change in the inflammatory milieu is a direct result of the altered metabolic environment, dictated by the MDR KP utilization of glucose and other energy- generating substrates. How the preferred metabolic pathways of selected bacteria determine inflammatory signaling is poorly understood. In our previous studies, we have found that the enhanced use of glucose by our representative MDR KP isolates gave the bacteria a fitness advantage in vivo, leading to persistence in the host lung. The long-term goal of this application is to understand how host immunity in the lung is influenced by the availability of scarce metabolites, as determined by both bacterial and host factors, resulting in bacterial persistence and/or impaired lung function. The central hypothesis of this application is that the availability of glucose in the lung dictates the inflammatory state of the lung in MDR KP infection and colonization. To address these questions, we propose to study the inflammatory cells and effectors, alongside the metabolic environment, in an in vivo model of pneumonia and airway washings of critically ill children dependent on ventilators. Our study design will allow us to execute the following aims: 1) We will determine how glucose utilization affects the immunometabolome in MDR KP pneumonia in vivo and 2) We will characterize the immunometabolome of airway washings from children with tracheostomies in baseline health and acute illness requiring admission to the PICU. Our multi-disciplinary approach is innovative in studying the mechanisms that drive the colonization of the airways by these opportunistic pathogens independent of antimicrobial resistance elements. The data acquired from this proposal will generate preliminary data for future more comprehensive funding mechanisms. In the future, this research will have a direct translational impact in determining the consequences of bacterial and immune cell metabolism on bacterial persistence in the airways, potentially improving ventilator-dependent children's lives.