SUMMARY The coagulopathy and inflammation of sepsis remain medical problems that are among the top five causes of human death. Those surviving severe sepsis and septic shock may further suffer lifelong debilitation with cognitive decline from the extensive vascular and organ damage of the host response. Decades of failure in the development of effective therapeutics for sepsis are reflected by the continuing high rate of mortality and the billions of dollars of healthcare costs expended on sepsis patient treatment each year. It has become evident that a greater understanding is needed of host factors that modulate the pathophysiology of this deadly syndrome. This project proposal is based on the recent discovery of a mechanism of glycoprotein senescence and turnover that operates in normal physiology to control the half-lives and abundance of multiple glycoproteins in the blood. Protein glycosylation creates multiple types of glycosidic linkages, including asparagine-linked N-glycans that are prevalent on blood glycoproteins. Preliminary data has revealed that N- glycans of blood glycoproteins are normally remodeled at a basal rate by circulating glycosidases during glycoprotein aging, resulting in the appearance of ligands for multiple endocytic lectin receptors. This host mechanism of glycoprotein senescence and turnover is altered in sepsis and has been demonstrated to affect disease outcome. Proposed studies include a focus on multiple specific glycosidases including mammalian neuraminidases, β-galactosidases, and β-N-acetylglucosaminidases that contribute to this innate mechanism of glycoprotein remodeling that regulates glycoprotein homeostasis and function. The research proposed includes corresponding lectin deficiency states to identify receptor-ligand relationships that alter pathogenesis. This project will utilize all of the core facilities proposed in this program while addressing the central hypothesis that protein glycosylation and glycoprotein remodeling modulate the coagulopathy and inflammation of sepsis. These studies will incorporate multiple bacterial pathogens spanning Gram-positive and Gram-negative organisms, and the findings will be compared to a model of the non-microbial Systemic Inflammatory Response Syndrome (SIRS). Mouse sepsis models as well as human sepsis patients with sepsis or SIRS will be studied for alterations in blood glycosidase expression and blood proteomes to link mechanisms of glycoprotein homeostasis and lectin receptor function with disease outcome. Preliminary data have identified multiple blood components regulated by this novel mechanism of glycoprotein senescence and turnover, and have established different disease pathways and molecular targets for therapeutic intervention. Findings further indicate that the pathogenesis of sepsis is not a singular disease process but is determined in part by the identities of bacterial pathogens involved. This has important implications in designing future therape...