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

总结 脓毒症是患者和临床医生面临的最常见和危及生命的综合征之一。往往 由于宿主反应在多个组织中引起的凝血病和炎症而致死， 幸存者可能因由此造成的血管和器官损伤而终身残疾。该项目的重点是 对这一重大健康问题，同时解决该计划的中心假设，即蛋白质糖基化 和糖蛋白重塑调节脓毒症的凝血病和炎症。最近有人 确定肝脏的肝细胞控制着循环分泌蛋白的丰度， 血栓形成和败血症期间的炎症。这是通过分泌蛋白质老化机制发生的， 包括内吞Ashwell-Morell受体（AMR）的细胞内翻。与先前描述的保护性 AMR在革兰氏阳性肺炎球菌感染引起的脓毒症中的作用， 确定AMR功能在革兰氏阴性细菌引起的脓毒症期间对宿主有害 病原体肠道沙门氏菌鼠伤寒（ST）。这些发现表明，AMR定位于 决定宿主对不同微生物病原体易感性的关系。这些发现进一步表明， 脓毒症的发病机制可以通过宿主对不同病原体的不同反应来分层， 推进脓毒症的理解，超越单一的疾病机制。本项目将调查 AMR功能的机制涉及Asgr 1和Asgr 2在宿主相互作用中参与 包括ST和大肠杆菌（EC）在内的革兰氏阴性细菌脓毒症的发病机制，以及平行研究 全身炎症反应综合征（SIRS）其他初步数据表明， AMR在高毒力菌株猪霍乱沙门氏菌（SC）感染后宿主结局中的功能， 最近发现的血清型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调节， 决定革兰氏阴性菌败血症的进展和结果，可能通过去磷酸化 和细菌脂多糖的解毒。AP同工酶在寄主-病原关系中的调控作用 由ST、SC和EC感染引起的脓毒症的相互作用将通过包括所有 提出的核心设施。拟议的研究将进一步确定AMR是否具有调节 目的是研究微生物的高毒力机制，包括比较SC感染引起的脓毒症。这 该项目将进一步确定脓毒症和SIRS中AMR调节的分泌蛋白的所有组成部分， 可能公开了新的生物标志物和蛋白质，其涉及调节细胞凋亡的其他机制。 凝血病和败血症炎症。这些研究可以将宿主对脓毒症的反应分层， 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.