PROJECT 2 - Mechanisms of Hypervirulence in the Pathogenesis of Sepsis

项目 2 - 脓毒症发病机制中的高毒力机制

• 批准号: 10171429
• 负责人: MICHAEL J MAHAN
• 金额: $ 46.07万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10171429
• 关键词: Address; Affect; Alkaline Phosphatase; Anti-Inflammatory Agents; Bacteria; Blood; Blood Circulation; Blood Coagulation Disorders; Blood Coagulation Factor; Bone Marrow; Cells; Clinical; Coagulation Process; Core Facility; Coupled; Cultured Cells; Data; Disease; Disease Outcome; Disseminated Intravascular Coagulation; Enzymes; Escherichia coli; Exhibits; Factor Analysis; Factor XI; Food Poisoning; Functional disorder; Generations; Genetic; Genetic Transcription; Glycobiology; Glycoproteins; Goals; Grant; Growth; Hematology; Host Defense; Human; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Innate Immune Response; Interleukin-10; Link; Molecular; Mus; Natural Selections; Nature; Neuraminidase; Organism; Osteomyelitis; Pathogenesis; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Pattern; Plasma; Production; Prognosis; Protein Glycosylation; Proteome; Proteomics; Research; Risk; Role; Salmonella; Salmonella typhimurium; Sepsis; Severities; Stratification; Testing; Therapeutic Agents; Variant; Virulence; Virulent; base; biomarker discovery; cytokine; design; diagnostic biomarker; enteric infection; gram-negative sepsis; macrophage; microbial; mortality; mutant; pathogen; programs; receptor; response; septic; septic patients

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.

项目摘要 目的解决了整个程序的中心假设：蛋白质糖基化和糖蛋白 重塑改变败血症的凝血病和炎症。拟议的研究基于新兴 败血症的标志，免疫系统施加的自然选择导致产生 高毒性应变变异，具有侵入性疾病的风险增加。据信高度毒气是由 病原体特异性决定剂和宿主反应的组合。在上一个赠款周期中，我们有 证明宿主对实验败血症的反应通过多种机制发生 在血液糖蛋白重塑中。拟议的研究重点是恶毒蛋白细菌和宿主的作用 糖蛋白重塑反应导致加速发作和凝血异常的进展 和败血症的炎症。该项目利用项目负责人和核心的综合专业知识 败血症病理生理学的主管，包括凝血，炎症，蛋白质组学和糖生物学 并参与该计划的所有核心设施。项目负责人发现了Hypervirus沙门氏菌 霍乱（SC）临床分离株是自然界中发现的最有毒的沙门氏菌之一。 SC通常 引起人类败血症或肠外感染，但与常见的食物毒品密切相关 病原体沙门氏菌伤寒（ST）。我们已经表明，在实验性ST和大肠杆菌败血症中，减少了 病原体选择宿主引起的抗炎饮酒线磷酸酶（AP）酶的血液水平 反应 - 神经辛酶活性（NEU）和最终的丙链酰化的诱导，并通过 Ashwell-Morell受体（AMR）。 AP降低减少LPS脱氧化，从而增加炎症 和死亡率。相比之下，我们最近的发现表明，SC不会引起NEU活动或AP清除， 但是AMR缺乏症仍然受到保护，暗示着其他宿主糖蛋白的参与，它们的参与 识别可能揭示了调节高温病毒和败血症的新途径和机制。额外的 初步数据表明，由于宿主水平降低，SC会引起促炎状态的增加 IL-10的诱导是一种影响脓毒症预后的免疫调节细胞因子。此外，分层 由革兰氏阴性病原体引起的实验和人败血症可能包括病原体选择性 调节循环中XI活性的调节。拟议的研究将识别和调查环境， 确定包括AMR，IL-10和凝结的遗传和蛋白质组学机制 因子XI及其在实验和人类败血症的分层和预后方面的效用。这 总体目标是确定病原体和宿主的组成部分和机制 毒力和败血症发病机理，导致诊断生物标志物发现和合理设计 几十年来一直发现发现的治疗剂。