Modifiable Determinants of Mortality in Neonatal Sepsis

项目总结 新生儿败血症是最困难和最昂贵的问题之一，需要治疗和预防。尽管有抗菌剂 治疗后，39%的败血症新生儿死亡或遭受严重的慢性疾病。尽管脓毒症死亡率和 发病率是双峰的，高峰出现在年龄的极端(非常年长和非常年轻)，调查 新生儿-宿主对败血症的免疫反应和不良长期结局背后的机制已经滞后 落后于年龄较大的儿童和成年人。早产儿在以下方面与更成熟的人群不同 基线免疫状态。例如，健康、未感染的人类新生儿血液循环水平升高。 与成人相比，IL-18在感染时表现出更多的IL-18产生。最近，我们展示了 IL-18缺失保护新生儿免于败血症死亡，反之，暴露于IL-18以模拟人类 早产会导致肠道损伤，全身炎症加剧，菌血症和死亡率增加。 在患有败血症的小鼠新生儿中。脓毒症小鼠暴露IL-18后，IL-17A转录早期升高 仅在肠道和肺部，血浆IL-17A蛋白水平是脓毒症小鼠的140倍 没有接触过IL-18。我们描述了一种新的早产儿有害炎症信号通路。 婴儿由IL-18引导，依赖IL-1R1信号，最终导致γδT过度产生IL-17A 对死亡负有机械责任的细胞。我们还证明了我们可以逆转IL-18- 通过药物阻断IL-17受体(IL-17R)增加脓毒症死亡率。我们现在展示的是这种疗法 与减少急性肺损伤(ALI)有关，急性肺损伤是人类新生儿死亡的倒数第二条途径。 本申请中提出的研究是治疗试验的先决条件，并将检验以下假设 IL-1α是导致肠道死亡和有害的IL-17A产生的主要配体，而IL-1β是 肺产生IL-17A的主要配体(目标1)，即γδT细胞产生IL-1R1依赖的IL-17A 在肠道和肺中都被IL-23增强(目标2)，ALI是一种主要的和可预防的机制 用于新生儿败血症并继发于原发肠道损伤的死亡(目标3)。首先，我们将确定IL- 1R1配体(S)与新生儿败血症时肠道和肺组织中IL-17A的产生及死亡率的关系 (目标1)。其次，我们将确定IL-23对IL-17A是否有额外的绝对要求 γδT细胞在肠道和肺中IL-1R1信号的下游产生(目标2)。最后，我们会 确定IL-17A是否是保护新生小鼠败血症所致急性肺损伤的理想治疗靶点 伤害(目标3)。累积起来，我们将寻找迄今为止未知的贡献者和监管者 途径，从而产生关于新生儿败血症鲜为人知的参数的新知识 通过测定IL-18/IL-1/IL-17A信号在脓毒症所致器官损伤中的作用。

PROJECT SUMMARY Neonatal sepsis is one of the most difficult and costly problems to treat and prevent. Despite antimicrobial therapy, 39% of neonates with sepsis die or suffer major chronic morbidity. Although sepsis mortality and morbidity is bimodal, with peaks at the extremes of age (very old and very young), investigations of the neonatal-host immune response to sepsis and the mechanisms behind poor long-term outcomes have lagged behind older children and adults. Preterm neonates differ from more mature populations in terms of their baseline immune status. For example, healthy, uninfected human neonates have elevated levels of circulating IL-18 when compared to adults and exhibit increased IL-18 production with infection. Recently, we showed that IL-18 deletion protected neonates from sepsis mortality and conversely, exposure to IL-18 to mimic the human preterm condition resulted in gut injury, enhanced systemic inflammation, increased bacteremia and mortality in murine neonates with sepsis. Following IL-18 exposure in septic mice, IL-17A transcript was elevated early and exclusively in the gut and lung, and plasma IL-17A protein was 140-fold greater than levels in septic mice without IL-18 exposure. We described a novel deleterious inflammatory signaling pathway in the preterm infant led by IL-18, dependent upon IL-1R1 signaling, and culminating in excessive IL-17A production by γδT cells that was mechanistically responsible for mortality. We also demonstrated that we could reverse IL-18- enhanced sepsis mortality via pharmacologic IL-17 receptor (IL-17R) blockade. We now show this treatment is associated with a reduction in acute lung injury (ALI), the penultimate pathway to death in human neonates. The studies proposed in this application are prerequisite to therapeutic trials and will test the hypotheses that IL-1α is the primary ligand that leads to mortality and deleterious IL-17A production in the gut while IL-1β is the primary ligand for IL-17A production in the lung (Aim 1), that IL-1R1-dependent IL-17A production by γδT cells in both the gut and the lung is augmented by IL-23 (Aim 2), and ALI is a principal and preventable mechanism for death in neonates with sepsis and is secondary to primary gut injury (Aim 3). First, we will determine the IL- 1R1 ligand(s) responsible for mortality and the production of IL-17A in the gut and lung during neonatal sepsis (Aim 1). Second, we will identify whether there is an additional absolute requirement of IL-23 for IL-17A production by γδT cells downstream from IL-1R1 signaling in the gut and in the lung (Aim 2). Finally, we will resolve whether IL-17A is an ideal therapeutic target to protect neonatal mice from sepsis-induced acute lung injury (Aim 3). Cumulatively, we will search for hitherto unknown contributors and regulators of this unique pathway and thus generate new knowledge about the poorly understood parameters of neonatal sepsis through determination of the role of IL-18/IL-1/IL-17A signaling in sepsis-induced organ injury.