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

项目摘要 脓毒症是一种危及生命的全身性炎症性疾病， 血液或组织中的微生物。在败血症期间， 炎症介质，包括细胞因子和活性氧，可导致血管 渗漏、弥散性血管内凝血和器官衰竭。在美国，败血症 每年有超过25万人死亡， 护理费用。临床上，脓毒症患者可以有可变的，往往是非特异性的体征和症状 这使得准确评估疾病严重程度或预测结果变得困难。这种可变性是 通常归因于个体遗传背景和免疫状态的差异。 hosts.然而，感染微生物的性质也会影响疾病的严重程度。株 肠外致病性大肠杆菌（ExPEC）是引起血液流变性的主要原因 感染和败血症的主要原因。同样致命的ExPEC分离物可以显著触发 不同的宿主反应，无论宿主背景特征如何。这些差异 与Toll样受体5（TLR5）的差异刺激相关， 血清型在这里，我们提出1）确定鞭毛蛋白变体是否影响严重性， 脓毒症的结果，2）确定鞭毛蛋白变体如何触发差异宿主反应，以及3） 定义鞭毛蛋白受体在脓毒症相关模型中的作用。这些研究将同时考虑 性别和年龄作为变量，重点是儿童中ExPEC诱导的脓毒症， 新生儿在本研究结束时，我们将对这些影响有一个清晰的机理性理解。 鞭毛蛋白变体和TLR5对ExPEC诱导的脓毒症的影响。这项工作将挑战 什么可以驱动败血症的体征和症状的变异性的流行观点， 因此有助于改进诊断工具和治疗方法的发展。

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.