Innate immune-mediated control of pulmonary Legionella pneumophila infection

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Project Summary Intracellular bacterial pathogens such as Legionella pneumophila, an important cause of community- and hospital-acquired pneumonia, are responsible for significant morbidity and mortality worldwide. As the spread of broad-spectrum antibiotic resistance among bacterial pathogens is escalating, discovery of novel innate immune defense mechanisms may hold the key for future therapeutic approaches to deal with this increasing threat. Intracellular pathogens deploy virulence factors to disable many immune cell functions. To win this battle, the host must overcome this subversion, through as yet poorly defined mechanisms. To address this critical gap in knowledge, we seek to define the parameters of successful innate immune clearance of Legionella. Legionella replicates within alveolar macrophages by using its type IV secretion system to deliver bacterial effectors, several of which inhibit host protein synthesis. Several effectors inhibit host protein synthesis. Despite this block in host translation, Legionella infection paradoxically enhances production of inflammatory cytokines. In the previous funding period, we demonstrated that Legionella-infected alveolar macrophages are able to synthesize and release IL-1; moreover, IL-1 receptor (IL-1R) signaling was required for robust production of TNF and IL-12 by bystander myeloid cells. Intriguingly, our newly published study show for the first time that IL-1R signaling in alveolar epithelial cells induces production of granulocyte-macrophage colony-stimulating factor (GM-CSF), which was required for bystander cytokine production and bacterial clearance. Intriguingly, while GM-CSF acts as a potent inflammatory cytokine in host defense against a broad spectrum of pathogens, our findings show for the first time that GM-CSF metabolically reprograms monocytes to undergo aerobic glycolysis, thereby promoting cytokine production. We will test the hypothesis that alveolar epithelium-derived GM-CSF metabolically reprograms monocytes to amplify epigenetic changes that enhance TLR-driven cytokine production and control of infection. In this renewal, we propose three Aims to first: define which cell types produce and respond to GM-CSF, second: understand the role of GM-CSF-mediated metabolic reprogramming in host defense, and third: define how GM-CSF and TLR signaling collaborate to promote cytokine production. Together, these studies will define novel innate immune mechanisms employed by the host to surmount pathogen-encoded virulence activities. The proposed research will therefore provide vital insight into mechanisms of host defense that are utilized against broad classes of microbial pathogens and aid development of improved anti-microbial therapeutics and vaccines.