Research Project
10171429
Project Summary The aims address the central hypothesis of the overall program: Protein glycosylation and glycoprotein remodeling alter the coagulopathy and inflammation of sepsis. Proposed research is based on the emerging hallmark of sepsis whereby natural selection imposed by the immune system results in the generation of hypervirulent strain variants with increased risk of invasive disease. Hypervirulence is believed to arise from a combination of pathogen-specific determinants and host responses. Over the last grant cycle, we have demonstrated that host responses to experimental sepsis occur by multiple mechanisms including alterations in blood glycoprotein remodeling. Proposed research focuses on the role of hypervirulent bacteria and host glycoprotein remodeling responses leading to accelerated onset and progression of coagulation abnormalities and inflammation of sepsis. This project utilizes the combined expertise of the Project Leaders and Core Directors in the pathophysiology of sepsis, including coagulation, inflammation, proteomics and glycobiology and engages all of the core facilities of the program. The Project Leader discovered hypervirulent Salmonella Choleraesuis (SC) clinical isolates that are among the most virulent Salmonella found in nature. SC typically causes sepsis or extra-intestinal infections in humans yet is closely related to the common food-poisoning pathogen Salmonella Typhimurium (ST). We have shown that in experimental ST and E. coli sepsis, reduced blood levels of anti-inflammatory alkaline phosphatase (AP) enzymes result from pathogen-selective host responses ? induction of neuraminidase activities (Neu) and resultant AP desialylation, and clearance by the Ashwell-Morell receptor (AMR). AP reductions diminish LPS de-toxification thereby increasing inflammation and mortality. In contrast, our recent findings indicate that SC does not induce Neu activities nor AP clearance, but AMR deficiency remains protective, implicating the involvement of other host glycoproteins, and their identification may reveal new pathways and mechanisms modulating hypervirulence and sepsis. Additional preliminary data suggest that SC elicits an increased pro-inflammatory state due to diminished levels of host induction of IL-10, an immune modulatory cytokine that affects sepsis disease outcome. Further, stratification of experimental and human sepsis caused by Gram-negative pathogens may include pathogen-selective modulation of Factor XI activity in circulation. Proposed research will identify and investigate environmental, genetic, and proteomic mechanisms determining hypervirulence including the AMR, IL-10, and coagulation Factor XI, and their utility in the stratification and prognosis of experimental and human sepsis. The overarching goal is to identify components and mechanisms of both the pathogen and host determining virulence and sepsis pathogenesis, leading to diagnostic biomarker discovery and rational design of therapeutic agents that have eluded discovery for decades.
