Protein Glycosylation in the Coagulopathy and Inflammation of Sepsis

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SUMMARY Sepsis is life-threatening syndrome caused by the presence of harmful microorganisms in the blood and tissues and resulting in host inflammation, coagulopathy and organ dysfunction. As the leading cause of death in non-cardiac intensive care units, the incidence of sepsis continues to increase while no new effective therapies have been developed in decades. Among patients, mortality averages 25%, while many survivors experience long-term disabilities caused by thrombosis, hypoperfusion, and hyperinflammation. Globally, sepsis is more prevalent than cancer with millions of patients and billions of dollars of health care costs annually. Lack of molecular information of the pathophysiology of sepsis has primarily contributed to the paucity of new and more effective treatments. This program project renewal proposal continues to address this problem with novel approaches to advance the knowledge of sepsis from a descriptive to a more molecular basis. The program retains the expertise of scientists and clinicians whom together are making transformative discoveries of disease mechanisms and protective strategies targeted by the pathogen and the host in the onset and progression of sepsis. The proposed program renewal leverages comparative models of experimental sepsis applied to the discovery of disease mechanisms that rapidly remodel and regulate host blood and vascular components. Remodeling includes glycosidic and proteolytic processes that cause profound changes to the half-lives, localization, abundance, and functions of circulating and cell surface glycoproteins and platelets, linked to the coagulopathy, inflammation, and lethality of sepsis. The program is integrated by the overall hypothesis that Protein glycosylation and glycoprotein remodeling alter the coagulopathy and inflammation of sepsis. The three projects and four core facilities proposed will address this hypothesis with synergistic, interdisciplinary, and state-of-the-art approaches. Aims of the projects and cores encompass comparative molecular investigations of coagulation factors, tissue thrombosis, inflammation, serology, and pathogen burden and virulence among blood, urine, and tissue proteomes. Findings thus far have identified mechanisms that differentially identify and alter sepsis in the context of discrete pathogens including changes in pathogen virulence, supporting the emerging view that sepsis does not arise from a singular disease mechanism and may be stratified to achieve diagnostic and therapeutic benefits. Comparative analyses of experimental and human sepsis will continue as findings thus far have indicated conserved markers of disease mechanisms linked to stratification by pathogen and patient prognosis. The rationale for the aims of this program are derived from extensive supporting data and recent peer-reviewed publications. Additional discoveries that this program is poised to make will enable further advances in the mechanistic understanding of the life-threatening changes to host blood and vascular systems during sepsis and generate significant insights needed to develop more effective diagnostics and therapeutics.