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 目标是解决整个计划的中心假设：蛋白质糖基化和糖蛋白 重塑改变凝血病和脓毒症的炎症。拟议的研究是基于新兴的 脓毒症的标志，其中免疫系统施加的自然选择导致产生 高毒力菌株变异，侵袭性疾病的风险增加。据信，超强毒力是由 病原体特异性决定簇和宿主反应的组合。在上一个赠款周期，我们有 表明宿主对实验性脓毒症的反应是通过多种机制发生的， 血液糖蛋白重塑建议的研究重点是超强毒力细菌和宿主的作用 糖蛋白重塑反应导致凝血异常加速发生和进展 和败血症的炎症。该项目利用项目领导和核心团队的综合专业知识， 脓毒症病理生理学的指导者，包括凝血，炎症，蛋白质组学和糖生物学 并使用该计划的所有核心设施。项目负责人发现高毒力沙门氏菌 猪霍乱（SC）临床分离株是自然界中发现的毒性最强的沙门氏菌之一。SC通常 引起人类败血症或肠外感染，但与常见的食物中毒密切相关 病原体鼠伤寒沙门氏菌（ST）。我们已经证明，在实验ST和E。大肠杆菌败血症，减少 血液中的抗炎性碱性磷酸酶（AP）水平由病原体选择性宿主引起， 反应-诱导神经氨酸酶活性（Neu）和由此产生的AP去唾液酸化，以及由 阿什韦尔-莫雷尔受体（AMR）。AP减少减少LPS去脂化，从而增加炎症 and mortality.相反，我们最近的研究结果表明，SC不诱导Neu活动，也不诱导AP清除， 但AMR缺乏仍然具有保护性，这意味着其他宿主糖蛋白的参与， 鉴定可能揭示调节高毒力和脓毒症的新途径和机制。额外 初步数据表明，由于宿主细胞内的细胞因子水平降低， 诱导IL-10，一种影响脓毒症疾病结果的免疫调节细胞因子。此外，分层 革兰氏阴性病原体引起的实验性和人类脓毒症可能包括病原体选择性 调节循环中的因子XI活性。拟议的研究将确定和调查环境， 决定高毒力的遗传和蛋白质组学机制，包括AMR、IL-10和凝血 因子XI及其在实验性和人类脓毒症分层和预后中的应用。的 总体目标是确定病原体和宿主决定的成分和机制 毒力和脓毒症发病机制，导致诊断生物标志物的发现和合理设计， 几十年来一直没有被发现的治疗药物。