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. PERFORMANCE SITE(S) (organization, city, slate) University of Iowa, Carver College of Medicine Iowa City, Iowa 52242 PHS 398 (Rev. 04/06) Page 200 Form Pago 2 Principal Investigator/Program Director (LasL First, Middle): Cook, Robert T., Research Component #2 KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required infonnalion in the fonnat shown below. start with Principal Investigator(s). List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Legge, Kevin L. klegge OTHER SIGNIFICANT CONTRIBUTORS Name Colgan, John D. Meyerholz, David K. Schlueter, Annette J. Varga, Steven M. Waldschmidt, Thomas J. Human Embryonic Stem Cells ^ No If the proposed project involves human embryonic Organization University of Iowa University of Iowa University of Iowa University of Iowa University of Iowa University of Iowa Principal Investigator Role on Project Collaborator Collaborator Collaborator Collaborator Collaborator Q Yes stem cells, list below the registration number of the specific cell llne(8) from the following list: http://stemcelis.nlh.a0V/reQistrv/index.asp. use continuation pages as needed. If a specific tine cannot be referenced at this time, include a statement that one from the Registry wrill be used. Cell Line PHS 398 (Rev. 04/06) Page 201 Form Pago 2-contlnued Number ttie following pages consecutively throughout the application. Oo not use suffixes such as 4a, 4b. Principal Investigator/Program Director (LasL First, Middle): Cook. Robert T.. Research Component #2 TABLE OF CONTENTS Page Numbers Research Compionent #2 Abstract and Key Personnel 200-201 Table of Contents 202 1. Specific Alms 203 2. Background and Significance 203-207 3. Preliminary Studies 207-211 4. Component Research Design and Methods 211-227 5. Resources and Environment 228 6. Human Subjects N/A 7. Vertebrate Animals 228-229 8. Literature Cited..,.. 229-234 9. Consortium/Contractual Arrangements N/A 10. Consultants/Collaborators 234 11. Letters of Support 235-239 Appendices on CD: 5 Publications PHS 398 (Rev. 04/06) Page 202 Fonn Page 3

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZAA1-BB (90))
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Jung, Kathy
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University of Iowa
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Hemann, Emily A; McGill, Jodi L; Legge, Kevin L (2014) Chronic ethanol exposure selectively inhibits the influenza-specific CD8 T cell response during influenza a virus infection. Alcohol Clin Exp Res 38:2403-13
Case, Adam J; McGill, Jodi L; Tygrett, Lorraine T et al. (2011) Elevated mitochondrial superoxide disrupts normal T cell development, impairing adaptive immune responses to an influenza challenge. Free Radic Biol Med 50:448-58
Langlois, Ryan A; Meyerholz, David K; Coleman, Ruth A et al. (2010) Oseltamivir treatment prevents the increased influenza virus disease severity and lethality occurring in chronic ethanol consuming mice. Alcohol Clin Exp Res 34:1425-31