Project 2: Host-Pathogen Interactions in Blood Glycoprotein Modulation of Sepsis

摘要 脓毒症是患者和临床医生面临的最常见、最危及生命的综合征之一。它经常是 致命的由于凝血障碍和炎症，在多个组织中引起的宿主反应，而 幸存者可能会因由此造成的血管和器官损伤而面临终身残疾。这个项目是专注于 关于这个主要的健康问题，同时解决了这个计划的中心假设，即蛋白质糖基化 糖蛋白重塑调节脓毒症的凝血和炎症反应。它最近一直在 确定肝脏的肝细胞控制调节循环的分泌蛋白的丰度 脓毒症期间的血栓形成和炎症。这是由于分泌的蛋白质老化和 周转率包括内吞的Ashwell-Morell受体(AMR)。与前面描述的保护性 AMR在革兰氏阳性肺炎球菌感染所致败血症中的作用，最近的初步数据 确定革兰氏阴性菌败血症时AMR功能对宿主有害 致病菌为鼠伤寒沙门氏菌(ST)。这些发现表明，AMR的定位是 NEXUS决定宿主对不同微生物病原体的敏感性。这些发现进一步表明， 脓毒症的发病机制可能是通过不同宿主对不同病原体的反应而分层的，这将 提高对脓毒症的认识，超越单一的疾病机制。该项目将调查 涉及Asgr1和Asgr2的AMR在参与宿主相互作用中的作用机制 革兰氏阴性杆菌败血症的发病机制：包括ST和大肠杆菌(EC)的平行研究 潜在的全身性炎症反应综合征(SIRS)。其他初步数据表明， AMR在超强毒力沙门氏菌感染后宿主结局中的作用 Serovar最近被发现是该物种中遇到的最致命的微生物之一。初步 数据表明，分泌的碱性磷酸酶同工酶受AMR的调节，这种调节 决定革兰氏阴性细菌败血症的进展和结局，可能是通过去磷酸化 细菌脂多糖的解毒作用。AP同工酶调节在寄主病原菌中的作用 ST、SC和EC感染引起的脓毒症的相互作用将通过包括所有 建议的核心设施。提出的研究将进一步确定AMR是否具有调制功能 AIMS中微生物超强毒力的机制，包括比较SC感染引起的败血症。这 该项目将进一步确定脓毒症和全身炎症反应综合征中受AMR调节的分泌蛋白质的谱系，这些蛋白质 可能会揭示新的生物标记物和蛋白质，这些标记和蛋白质涉及调节 脓毒症的凝血障碍和炎症。这些研究可能将宿主对脓毒症的反应分层，涉及 AMR和不同的病原体，同时确定导致诊断和治疗进展的机制。

SUMMARY 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.