Impact of Aging on Oxysterol Regulation of Alveolar Macrophage Function during S. pneumoniae

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Project Abstract Normal lung aging is associated with multiple structural and functional changes in the respiratory tract. Alveolar macrophages (AM) are long-lived tissue resident innate immune cells of the airways and during steady state conditions, adopt a pro-healing, anti-inflammatory phenotype to maintain lung integrity. AM are key effectors of recognition, initiation, and resolution of the host defense against microbes and play an essential role in mediating host responses to Streptococcus pneumoniae (S. pne). Cell essential and macrophage aged death and the effective clearance of dying cells are processes t hat maintain tissue homeostasis. When efferocytosis is defective, increased tissue injury development of acute respiratory distress syndrome (ARDS) can occur. Despite defects in alveolar phagocytosis being prevalent i n aging, very little is known on how the process of aging and the lung microenvironment contribute to these changes.Our published findings illustrate that an age- associated increase in mitochondrial and endoplasmic reticulum stress during S. pne contributed to dysregulated, overly heightened pro-inflammatory immune responses in AM and lung. To better understand the metabolic factors that might contribute to this phenotype, we examined changes in lipid metabolism in young and aged lung. We observed a molecular reprogramming in response to dysregulated cholesterol homeostasis. Given these findings, we hypothesize that an age-associated increase in lipid metabolism alters innate immune responsiveness and efferocytosis by AMs, thereby contributing to heightened inflammation and prolonged tissue injury in response to S. pne. To test this hypothesis, we have designed three specific aims that will utilize innovative techniques to spatially landscape landscape the mediated utilize the will the resolve single-cell data that will allow us to develop a biologically interpretable of lung pathology from a structural, immunological, and clinical standpoint. This spatial single-cell will enable the pathophysiological characterization of the lung from its macroscopic presentation to single-cell, providing an important basis for the understanding of lipid metabolism on alveolar macrophage process and will provide insights into age-associated changes in lung pathology. In addition, we will metagenomic sequencing of human plasma to distinguish infection and infectious disease, and to assess severity of pneumococcal disease. We firmly believe that fundamental insights gained from this novel assay be applicable to other infection models and will help clarify many of the long-outstanding questions regarding role of aging on specific tissue responses.