The long-term objective of this project is to understand the mechanisms of alcohol-induced immunosuppression and how such immunosuppression predisposes to infection or interacts with other immunosuppressive diseases such as HIV infection. Preliminary data from our laboratory indicate that alcohol consumption increases mortality in a murine model of Klebsiella pneumonia, and impairs recruitment of neutrophils into lung tissue in response to the infectious challenge. We postulate that neutrophil recruitment is amplified through the release of the lymphocyte-derived cytokine, Interleukin-17 (IL-17). Preliminary data show that local release of IL-17 is impaired in the alcohol-consuming mice challenged with Klebsiella pneumoniae. In this project, we will test the experimental hypothesis that alcohol consumption suppresses host release of IL-17 by pulmonary T-lymphocytes in response to an infectious challenge leading to impaired release of chemotactic cytokines, compromised recruitment of neutrophils into lung tissue, and more severe infection.
In Specific Aim 1, we will localize IL-17 to CD4+ and CD8+ T-lymphocytes in the interstitium or alveolar space at serial intervals after bacterial challenge using flow cytometry and laser capture microdissection in control and alcohol-consuming mice. Additional experiments will test glutathione depletion as a mechanism for the suppressive effect of alcohol on release of IL-17.
In Specific Aim 2, we will show that alcohol-induced suppression of IL-17 leads to diminished host release of CXC chemokines and consequent decreased recruitment of neutrophils in response to K. Pneumoniae.
In Specific Aim 3, we will confirm that decreased host resistance to infection in alcohol-consuming mice is due to suppression of IL-17 by upregulating IL-17 in lung tissue. Experiments will utilize in vivo transfer of the IL-17 gene into alcohol-treated mice to restore defects in neutrophil recruitment and augment host defense against bacteria infection in spite of continued alcohol consumption. The results of these experiments will provide new information on how alcohol interferes with host defense against bacterial pneumonia and may lead to novel approaches to augment immune function in alcoholic as well as HIV-infected hosts.
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