The Role of the Inflammasome in Neonatal Sepsis

描述（由申请人提供）：新生儿败血症是治疗和预防最困难和最昂贵的问题之一。尽管接受了抗菌药物治疗，39%的新生儿败血症死亡或出现严重的慢性疾病。新生儿-宿主对败血症的免疫反应及其对不良长期结局的影响的调查落后于年龄较大的儿童和成人。在我的奖学金培训期间，我开发并验证了一个临床相关的新生儿多微生物脓毒症小鼠模型，以分析新生儿对脓毒症引起的药物的特异性免疫反应。我们发现新生儿表现出先天免疫反应减弱，与年轻人相比更容易患败血症。具体来说，脓毒症小鼠新生儿产生的IL-1¿比成年鼠少60倍。IL-1的产生对先天免疫细胞功能至关重要，与炎性体功能密切相关。因此，我们建议使用缺乏关键炎症小体成分的转基因敲除小鼠来探索炎症小体信号在小鼠新生儿脓毒症中的作用。接下来，我们将确定先天性免疫受体（TLRs）激活后，新生儿和成人在炎症小体上游和下游信号传导（炎症小体特异性mRNA表达和蛋白质产生）方面的差异。最后，我们将确定增强炎性体激活（使用基因敲入人源化小鼠）或其成熟（活性）产品（IL-1¿，IL-18）作为新生儿败血症的潜在治疗方法的作用。总之，我们将在个体发育过程中寻找迄今为止未知的炎性体发育特征，并通过确定炎性体信号传导的作用，对目前尚不清楚的新生儿脓毒症参数产生新的认识。因此，确定炎症小体成分特异性缺乏对新生儿和成人败血症的影响，并提供它们在新生儿败血症易感性和结局中的潜在重要性的直接证据，将有助于我们的研究

DESCRIPTION (provided by applicant): 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. Investigations of the neonatal-host immune response to sepsis and its impact on poor long-term outcomes have lagged behind older children and adults. During my fellowship training I developed and validated a clinically-relevant neonatal murine model of polymicrobial sepsis to analyze the neonatal-specific immune response to sepsis-causing agents. We found that neonates exhibit an attenuated innate immune response and are more susceptible to sepsis compared to young adults. Specifically, septic murine neonates produced up to 60 times less IL-1¿ than adults. IL-1¿ production, critical for innate immune cellular function, is intimately linked to inflammasome function. Therefore, we propose to explore the role of inflammasome signaling during murine neonatal sepsis using transgenic knockout mice lacking key inflammasome components. Next, we will determine the differences between neonates and adults in upstream and downstream inflammasome signaling (inflammasome-specific mRNA expression and protein production) following activation of innate immunity receptors (TLRs). Lastly, we will determine the role of enhanced inflammasome activation (using a genetic knock-in humanized mouse) or administration of its mature (active) products (IL-1¿, IL-18) as potential therapies for neonatal sepsis. Cumulatively, we will search for hitherto unknown features of inflammasome development during ontogeny and generate new knowledge about currently poorly understood parameters of the neonatal sepsis through determination of the role of inflammasome signaling. Thus, determining the impact of specific deficiencies in inflammasome components on neonatal vs. adult sepsis and providing direct proof about their potential importance in the susceptibility to and outcome of neonatal sepsis will represent major advance in this research front. Moreover, this investigation will help in the development of much needed biomarkers for neonatal sepsis susceptibility and identification of novel targets for therapy, such as inflammasome gain-offunction immunotherapy directed at improving sepsis outcomes. We will identify the differences in inflammasome signaling intermediates that result in the large discrepancy in IL-1¿ production between septic neonates and adults. Identification of mechanism(s) behind this large difference will allow development of targeted approaches that may lead to improved outcomes. We will thus explore the potential for translational value of inflammasome activation or for provision of its mature products as novel immunotherapies for neonatal sepsis in the aftermath of the negative outcome of intravenous immunoglobulin therapy for neonatal sepsis in a recent multicenter trial (NEJM 2011). We surmise that our focus on one of the most challenging problems in neonatology is consistent with the NIGMS' strategic mission to develop the foundation for advances in disease diagnosis, treatment and prevention as well as development of the next generation of physician-scientists.