Impact of Flagellin Variants and Receptors on the Progression and Outcome of Sepsis

鞭毛蛋白变异体和受体对脓毒症进展和结果的影响

• 批准号: 9811363
• 负责人: MATTHEW A MULVEY
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9811363
• 关键词: Address; Affect; Age; Animal Model; Biochemical; Bioinformatics; Biological Assay; Blood Circulation; Blood Vessels; Characteristics; Child; Clinical; Coupled; Data; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Disseminated Intravascular Coagulation; Ensure; Extravasation; Flagella; Flagellin; Follow-Up Studies; Gene Expression Profiling; Generations; Genetic; Health Care Costs; Human; Immune response; Individual; Infant; Infection; Inflammation Mediators; Inflammatory; Inflammatory Response; Integration Host Factors; Life; Light; Link; Microbe; Modeling; Mus; Nature; Newborn Animals; Organ failure; Organelles; Outcome; Patient-Focused Outcomes; Patients; Pattern recognition receptor; Proteins; Reactive Oxygen Species; Reporter; Research; Role; Sepsis; Serotyping; Severities; Severity of illness; Signal Transduction; Signaling Molecule; Signs and Symptoms; Structure; Syndrome; TLR5 gene; Therapeutic; Tissues; Toll-like receptors; United States; Variant; Work; Zebrafish; cell motility; clinically relevant; cost; cytokine; genetic variant; imaging approach; immunological status; improved; individual patient; insight; knockout animal; mature animal; microorganism; neonate; novel therapeutics; outcome prediction; pathogen; pathogenic Escherichia coli; receptor; septic; septic patients; sex; tool

PROJECT SUMMARY Sepsis is a life-threatening systemic inflammatory condition that is initiated by the presence of microorganisms in the bloodstream or tissues. During sepsis, the generation of excessive inflammatory mediators, including cytokines and reactive oxygen species, can result in vascular leakage, disseminated intravascular coagulation, and organ failure. In the United States, sepsis kills over a quarter of a million people each year and is associated with extremely high health care costs. Clinically, sepsis patients can have variable, often non-specific signs and symptoms that make it difficult to accurately assess disease severity or predict outcomes. This variability is frequently attributed to differences in the genetic background and immune status of individual hosts. However, the nature of the infecting microbes can also impact disease severity. Strains of Extraintestinal Pathogenic Escherichia coli (ExPEC) are the principal cause of bloodstream infections and a leading cause of sepsis. Similarly lethal ExPEC isolates can trigger markedly different host responses, irrespective of host background characteristics. These variances correlate with differential stimulation of Toll-Like Receptor 5 (TLR5) by discrete flagellar serotypes. Here we propose to 1) determine if flagellin variants influence the severity and outcomes of sepsis, 2) establish how flagellin variants trigger differential host responses, and 3) define roles for flagellin receptors in relevant models of sepsis. These studies will consider both sex and age as variables, with an emphasis on ExPEC-induced sepsis in children and neonates. By the end of this study we will have a clear mechanistic understanding of the effects that flagellin variants and TLR5 have on ExPEC-induced sepsis. This work will challenge prevailing views of what can drive variability in the signs and symptoms of sepsis and will consequently aid the development of improved diagnostic tools and therapeutics.

项目摘要 败血症是一种威胁生命的全身性炎症状况，由存在引发 血液或组织中的微生物。败血症期间，过度产生 炎症介质，包括细胞因子和活性氧，可能导致血管 泄漏，散布的血管内凝结和器官衰竭。在美国，败血症 每年杀死四分之一以上的人中的四分之一，与健康相关 护理费用。在临床上，败血症患者可能具有可变的，通常是非特异性体征和症状 这使得难以准确评估疾病的严重程度或预测结果。这种可变性是 通常归因于遗传背景和个人免疫状态的差异 主持人。但是，感染微生物的性质也会影响疾病的严重程度。菌株 肠外致病性大肠杆菌（Expec）是血液的主要原因 感染和败血症的主要原因。同样，致命的expec隔离株可以明显触发 不同的主机响应，无论主机背景特征如何。这些差异 与离散的鞭毛对Toll样受体5（TLR5）的差异刺激相关 血清型。在这里，我们建议1）确定鞭毛蛋白变体是否影响严重程度和 败血症的结果，2）建立鞭毛蛋白变体如何触发差异宿主反应，3） 定义鞭毛蛋白受体在相关模型中的作用。这些研究将同时考虑 性别和年龄作为变量，重点是儿童的败血症， 新生儿。在这项研究结束时，我们将对影响有清晰的机械理解 该鞭毛蛋白变体和TLR5在指示引起的败血症上具有。这项工作将挑战 关于败血症的体征和症状可变可变性的盛行的观点 因此，有助于开发改进的诊断工具和治疗剂。