Pneumonia is one of the leading causes of morbidity and mortality, particularly in older individuals. Importantly, alcohol misuse has been associated with increased pneumonia for over 200 years. While the role of alcohol in bacterial pneumonia susceptibility and severity remains to be fully understood, it is essential to define the at- risk conditions and unique needs of those who misuse alcohol and to do so immediately to optimize clinical care. Disease is impacted by the sum of all environmental exposures during one’s life. Collectively referred to as the exposome, little alcohol-mediated lung injury has taken into consideration such real-world complexity. In this 5-year project, we will investigate the alcohol exposome in lung bacterial infections. Compared to the general public, those with alcohol use disorders (AUD) can be characterized by heavy cigarette smoking leading to pre-existing lung diseases such as chronic obstructive pulmonary disease (COPD), a major co- morbidity for pneumonia. Likewise, nutritional deficiencies play an important role in disease pathogenesis. Our knowledge about how such exposome characteristics impact alcohol-mediated lung injury is limited. However, results from our previous lung alcohol research have already demonstrated that AUD are associated with cilia dysfunction. Our results also demonstrate that AUD results in decreased surfactant anti-microbial action. Surfactant protein D has been documented to specifically bind to and aggregate bacteria for optimal microbicidal action. We hypothesize that altered innate lung defense at the level of mucociliary clearance and anti-microbial surfactants will negatively impact susceptibility and pathogenesis of bacterial pneumonia, placing individuals with AUD particularly in harm’s way. Our assembled team of investigators include a VA Research Career Scientist with 26 years’ experience in the impact of alcohol on lung injury and repair, a pulmonologist whose expertise is on characterizing primary human lung clinical samples, experienced alcohol liver injury researcher with extracellular vesicle expertise, a senior professor of pharmacy recognized internationally as a zinc expert, and a junior investigator who is already an expert in alcohol-mediated gut dysbiosis and bacterial infections. Our established expertise in mouse models of alcohol injury combined with our existing biobank of human lung cells and tissues, we propose to address our hypothesis by identifying any differences in S. pneumoniae infection responses due to a complex exposome model of alcohol, cigarette smoking, and zinc deficiency. We will specifically identify in these groups any changes in cilia beat controlling clearance and the role of reactive aldehydes generated by liver- and gut-derived extracellular vesicles. Such studies will be performed for the first time in animal and cell models relevant to AUD. Defining the modalities of risk will also empower clinicians to make informed preventive care de...