Alcohol abuse is a leading cause of disease and death in the United States. Alcohol consumption impairs lung defense and increases the risk of bacterial pneumonia. Alcohol users with pneumonia respond poorly to antibiotics, experience more severe symptoms and higher rates of mortality. Mucociliary clearance (MCC) is a primary lung defense mechanism against inhaled/aspirated pathogens and is impaired by excessive alcohol use. Unfortunately, our limited understanding of alcohol effects has prevented the development of interventions to reverse mucociliary dysfunction and augment host immunity against infections. Recently, we reported that alcohol reduces ion transport function of CFTR, the defective channel that causes cystic fibrosis lung disease, which is also characterized by diminished MCC and frequent infections. Supporting this discovery, patients with alcohol-induced pancreatitis (another disorder that is causally linked with CFTR defects) were found to exhibit lower CFTR activity even after they abstained from drinking. Of note, these patients had normal CFTR genetics excluding the role of inherited defects and thus, confirming the phenomenon of ‘acquired CFTR dysfunction’. Our preliminary studies in rat model of chronic alcohol administration detected substantially reduced CFTR ion transport, increased mucus viscosity and, dramatically decreased MCC. When compared to their pair-fed controls, alcohol-treated rats failed to clear Klebsiella pneumoniae and, exhibited histopathologic evidence of severe pneumonia. Our data indicate alcohol increases the activity of phosphodiesterase-4B (PDE4B) enzyme that specifically degrades cAMP causing reduced PKA-dependent phosphorylation and opening of CFTR ion channels. Moreover, we demonstrate that roflumilast, a clinically used PDE4 inhibitor, is successful in restoring cAMP levels in alcohol-treated cells and reversing CFTR dysfunction and mucus abnormalities in alcohol-treated rats. Guided by these strong preliminary data, we propose to pursue three Specific Aims to investigate how alcohol-induced CFTR dysfunction may cause susceptibility to bacteria pneumonia: (1) Determine the specific contribution of reduced CFTR function to alcohol-induced defects in mucociliary clearance. (2) Determine the molecular mechanisms underlying alcohol-induced CFTR dysfunction. (3) Determine the clinical benefits of reversing alcohol-induced CFTR dysfunction towards preventing bacterial pneumonia. Collectively, our proposed research will broadly impact the field by characterizing the essential role of CFTR dysfunction in compromising lung defense in alcohol users. These studies will have the potential to uncover novel molecular mechanisms underlying bacterial pneumonia as well as advance new treatment approaches to reduce disease burden. These findings may be extrapolated to other non-pulmonary alcohol use disorders such as pancreatitis, diabetes and infertility, where there are similar therapeutic needs and knowledge g...