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

项目总结 脓毒症是一种危及生命的全身性炎症状态，由 血液或组织中的微生物。在脓毒症期间，产生过量的 炎症介质，包括细胞因子和活性氧物种，可导致血管 渗漏、弥漫性血管内凝血和器官衰竭。在美国，败血症 每年导致超过25万人死亡，与极高的健康水平有关 护理费用。临床上，脓毒症患者可以有不同的、通常是非特异性的体征和症状。 这使得准确评估疾病严重性或预测结果变得困难。这种可变性是 经常归因于个体遗传背景和免疫状态的差异 主持人。然而，感染微生物的性质也会影响疾病的严重性。品系 肠外致病性大肠埃希菌(ExPEC)是引起血流的主要原因 感染和败血症的主要原因。同样致命的ExPEC分离株可以显著地引发 不同的主机响应，与主机背景特性无关。这些差异 离散鞭毛对Toll样受体5的差异性刺激作用 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 败血症的后果，2)确定鞭毛蛋白变体如何触发不同的宿主反应，以及3) 明确鞭毛蛋白受体在相关脓毒症模型中的作用。这些研究将考虑到这两个因素 性别和年龄作为变量，重点关注ExPEC引起的儿童脓毒症和 新生儿。在这项研究结束时，我们将对这些影响有一个明确的机制理解 鞭毛蛋白突变体和TLR5在ExPEC诱导的脓毒症中的作用。这项工作将具有挑战性 关于脓毒症的体征和症状以及意志的可变性的普遍观点 从而帮助开发改进的诊断工具和治疗方法。

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.