Sepsis is a significant public health issue in the United States, killing 300,000 people each year and generating over $60 billion in costs to Medicare beneficiaries. Because we do not fully understand how infection triggers the inflammatory dysregulation seen in sepsis, no targeted therapies for sepsis are clinically available. Patient treatments are limited to antibiotics directed against infection and supportive care for organ failure. Cell death signaling pathways, the mechanisms that control cell fate in response to environmental stimuli, are distributed throughout mammalian tissue and are a foundational component of host defense against invading pathogens. During infection, these pathways activate immune responses, clear infected cells, incite tissue damage, and promote inflammation. This proposal seeks to understand how cell death signaling pathways contribute to the inflammatory dysregulation that typifies sepsis. This will be done by assaying activity of these pathways under conditions of infection in both immune and non-immune tissue. Samples collected from septic human patients will be analyzed for cell death signaling pathway activity and data will be correlated with clinical variables. Insights gained from these observations will be used to direct mechanistic studies aimed at determining how these pathways are regulated during sepsis. Both in vitro and in vivo techniques will be utilized when experiments cannot be performed in human patients. Cultured human cell lines will be infected and analyzed in vitro, and the effects of cell death signaling pathway inhibition will be measured in septic animals. Results from this proposal will better define the mechanisms through which infection unleashes dysregulated inflammation in sepsis and offer a greater understanding of how core cellular homeostasis and defense machinery functions during critical illness. This knowledge stands to produce novel therapeutic strategies and targets for a deadly disease process that continues to put tremendous strain on modern healthcare systems.