Immune activation during severe infection is accompanied by widespread lymphocyte apoptosis. In animal models of lethal infection, lymphocyte apoptosis appears to compromise the host, as strategies to oppose apoptosis improve survival. Alcoholism is associated with an increased risk of severe infection, and depletion of lymphocytes in spleen and thymus dudng chronic ethanol consumption is well recognized. Because ethanol and infection can increase oxidative stress to mitochondria, and mitochondria are central regulators of apoptosis, we hypothesize that ethanol consumption increases mitochondrial injury and death signaling in lymphocytes during infection. We propose to study the effects of chronic ethanol exposure on lymphoid tissue injury during infection with Streptococcus pneumoniae, a common cause of bacteremia in alcoholism and HIV infection.
In Specific Aim 1, we will determine the effects of ethanol feeding on apoptosis in 1) spleen and thymus during pneumococcal infection in vivo and 2) splenocytes exposed to a relevant death signal, Fas ligand, in vitro.
In Specific Aim 2, we will measure the effects of ethanol feeding and pneumococcal infection on mitochondrial glutathione content and oxidative injury to mitochondrial DNA in lymphoid tissue.
In Specific Aim 3, we will evaluate two mitochondria-based strategies for opposing lymphocyte apoptosis in this model by 1) utilizing bcl-2 over-expressing transgenic mice and 2) supplementing mitochondrial glutathione. The results of these experiments will increase our understanding of how chronic ethanol exposure compromises lymphoid tissues directly and during the acute stress of infection.
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