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 bacterial pneumonias. 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 studies indicate that chronic consumption of EtOH increases both influenza virus associated morbidity and mortality. Further, our results demonstrate that this increased severity of disease is related to defects or alteration in influenza-specific CD8 T cell responses as well as respiratory dendritic cells (rDC). Importantly our findings of severe disease and poor outcomes using the Meadows-Cook model of EtOH consumption have been supported by a recent study in humans which showed that heavy alcohol use is a risk factor for severe outcomes during influenza virus infections. Therefore given the current threat of both epidemic and potential 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 in these individuals. 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 contributions of the EtOH induced environment vs. T cell intrinsic lesions in the reduced CD8 T cell immunity during primary influenza virus infections of the chronic EtOH lung. Further as the CD8 T cell response in non immunologically naive individuals is made up of both new nave T cell responses as well as existing T cell memory, this application will be the first t determine how chronic EtOH alters CD8 T cell memory that has been established prior to chronic EtOH consumption. Our central hypothesis is that the chronic EtOH induced lesion in the primary CD8 T cell response is made up of both environmental and T cell intrinsic defects and that chronic EtOH will reduce existing CD8 T cell memory. We propose the following Specific Aims: 1) Determine the contribution of environmental vs. T cell intrinsic factors to the EtOH induced lesion in the primary IAV-specific CD8 T cell response, 2) Determine how chronic ethanol consumption alters existing influenza-specific CD8 T cell memory and heterosubtypic protection against influenza virus infections. This application will not only define the defects tht 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.

Public Health Relevance

While many studies have detailed the increase in disease severity during respiratory infections in alcoholics, much less is understood about the underlying mechanisms through which chronic ethanol (EtOH) consumption mediates this increase in disease severity or how alcohol alters pulmonary adaptive immune responses. This project will detail the lesions within and the mechanisms controlling the respiratory adaptive immune responses to influenza virus (IAV) determine the underlying cause of these lesions. A better understanding of the alcohol induced lesions within the pulmonary adaptive immune response could lead to methodologies to boost immunity to this important human pathogen in these individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AA024860-02
Application #
9269492
Study Section
National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
Program Officer
Lin, Li
Project Start
2016-05-05
Project End
2018-10-31
Budget Start
2017-05-01
Budget End
2018-10-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pathology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242