Sepsis is one of the most common and life-threatening syndromes faced by patients and clinicians. It is often fatal due to the coagulopathy and inflammation that arises in multiple tissues from the host response, while survivors may face a lifetime of disability from the resulting vascular and organ damage. This project is focused on this major health problem while addressing the central hypothesis of this program, that protein glycosylation and glycoprotein remodeling modulate the coagulopathy and inflammation of sepsis. It has recently been determined that hepatocytes of the liver control the abundance of circulating secreted proteins that modulate thrombosis and inflammation during sepsis. This occurs by a mechanism of secreted protein aging and turnover that includes the endocytic Ashwell-Morell receptor (AMR). Unlike the previously described protective role of the AMR in sepsis caused by Gram-positive pneumococcal infection, preliminary data have recently determined that AMR function is deleterious to the host during sepsis caused by the Gram-negative bacterial pathogen Salmonella enterica Typhimurium (ST). These findings suggest that the AMR is positioned at a nexus determining host susceptibility to different microbial pathogens. These findings further indicate that the pathogenesis of sepsis may be stratified by different host responses to different pathogens, which would advance the understanding of sepsis beyond that of a singular disease mechanism. This project will investigate the mechanisms of AMR function involving Asgr1 and Asgr2 in host interactions that participate in the pathogenesis of Gram-negative bacterial sepsis to include ST and Escherichia coli (EC), with parallel studies of the underlying Systemic Inflammatory Response Syndrome (SIRS). Other preliminary data indicate a role of AMR function in host outcomes following infection by the hypervirulent strain Salmonella Choleraesuis (SC), a serovar recently discovered to be among the most virulent microbes encountered of this species. Preliminary data indicate that secreted alkaline phosphatase isozymes are regulated by the AMR and that this regulation determines the progression and outcome of Gram-negative bacterial sepsis, perhaps by dephosphorylation and detoxification of bacterial lipopolysaccharide. The roles of AP isozyme regulation in host-pathogen interactions of sepsis caused by ST, SC, and EC infection will be determined by research that includes all of the core facilities proposed. Studies proposed will further determine whether the AMR functions to modulate mechanisms of microbial hypervirulence in aims that include comparing sepsis caused by SC infection. This project will further identify the repertoire of secreted proteins regulated by the AMR in sepsis and SIRS, which may disclose novel biomarkers and proteins that are implicated in additional mechanisms that modulate the coagulopathy and inflammation of sepsis. These studies may stratify host responses to sepsis involving the AMR and different pathogens while identifying mechanisms that lead to diagnostic and therapeutic advances.
The coagulopathy and inflammation of sepsis are major causes of human disability and death with millions of people affected in the U.S. each year. Death as an outcome still averages 30%, underscoring the incomplete knowledge of host-pathogen interactions and the need for breakthroughs in biomedical research of this long- standing problem. This research proposal will focus on newly discovered and previously understudied biological mechanisms operating in the host that modulate the coagulopathy and inflammation of this deadly syndrome in order to transform the understanding and treatment of sepsis.
