Chronic alcohol and pulmonary immunity

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Chronic alcoholism increases the incidence and severity of respiratory diseases and infections. Indeed, alcoholics compared to non-alcoholic individuals have increased mortality and morbidity during bacterialpneumonias. While much is known about the role that chronic alcohol plays in increasing the severity of respiratory bacterial infections, much less is understood about how chronic ethanol (EtOH) consumption alters the severity of pulmonary virus infections. Interestingly, our preliminary studies indicate that chronic EtOH increases both the morbidity and mortality of influenza A virus infections. Further our results suggest that the increased severity of disease may relate to defects or alterations in both respiratory dendritic cells as well as influenza-specific CDS T cell responses. Given the current threat of both epidemic and pandemic influenza a better understanding of the lesions within the pulmonary adaptive immune response in chronic alcoholics could lead to methodologies to boost immunity to this Important human pathogen. Therefore our long-range goal is to determine what lesions chronic EtOH induces within the respiratory adaptive immune response. Within this application we will continue to use the Meadow-Cook chronic EtOH model as well as our mouse models of influenza virus infection to determine the EtOH associated lesions that occur within respiratory dendritic cells and influenza-specific CDS T cells. Our central hypothesis is that defects within both respiratory dendritic cell function and CDS T cell responses are responsible for the observed increased severity of influenza virus infections in chronic EtOH mice. We propose the following Specific Aims: 1) Determination of the lesion within the resting pulmonary immune system of chronic EtOH mice 2) Determination of the pathogenicity of influenza- infection in chronic EtOH mice 3) Detennination of the role of DC in chronic EtOH enhanced influenza-associated pathology 4) Determination of the rple of influenza-specific CDS T cell immunity in enhanced disease in chronic EtOH mice. This proposal will not only define the defects that chronic EtOH creates In pulmonary adaptive immunity during respiratory virus infections but should also increase our understanding of immunity during other (bacterial/fungal) respiratory infections. Furthermore, the insights learned from this proposal hold the potential to suggest methodologies to restore and/or boost immunity in chronic alcoholics during these diseases.