Neonatal immune response to gut originating pathogens

项目摘要 晚发性败血症（LOS）是一种血流感染，是新生儿死亡的主要原因， 占所有新生儿死亡的26%，是早产儿的主要威胁。加强卫生习惯 未能大幅降低LOS发生率，在过去的四十年里， 由于医疗技术的提高，早产儿的存活年龄不断降低， 婴儿。目前，LOS是用静脉注射抗生素治疗的，但抗生素耐药菌正在成为 更大的关注。此外，LOS患者发生长期认知发育问题的风险更大。 在LOS的相当一部分，病原体可以作为新生儿肠道微生物群落的居民被发现 然而，对于LOS最初如何发展的不完全理解以及缺乏动物模型， 探讨LOS的发病机制、治疗和预防是该领域研究进展的障碍。此外，委员会认为， 由正常皮肤和肠道植物群成员引起的LOS病例的增加趋势迫使 探索败血症病原体的定义。然而，目前尚不清楚：1）肠道病原体如何 传播和2）呼吸和器官衰竭的后续原因，导致死亡 LOS。人们一直认为，新生儿的反应是不成熟和无知，缺乏能力， 由于免疫抑制状态而适当地对抗细菌病原体，直到免疫系统完全成熟， 导致新生儿被全身性细菌复制和毒素产生压倒。我有 开发了一种动物模型，由此中断同步母乳喂养导致肠道易位 病原体从肠道进入系统，导致败血症。我将利用这个模型来探索免疫 在新生儿中的反应，并使用外周来源的白细胞将这些发现转化为人类， 婴儿血液样本中的淋巴细胞。我的假设，与目前新生儿免疫的观点相反， 基于新生儿特有的细胞因子特征的最新临床发现， 血清IL-6是新生儿在全身性细菌感染后产生大量细胞因子应答。 此外，人类数据显示，脓毒症病原体在4%内促进T细胞的非特异性活化。 小时，表明IL-6和淋巴细胞的非特异性活化的组合可能导致细胞因子 把线索捅到死该项目将利用动物模型，人类血液样本，败血症病原体， 多种基于流式细胞术的测定来探索对脓毒症病原体的免疫应答。后 完成这个项目，我将了解什么是系统性细菌感染的下游反应， 新生儿是由，这将允许进一步探讨如何细菌成分独特的败血症 病原体引起大量细胞因子反应。此外，这项工作将有助于制定干预措施， 和预防性治疗新生儿败血症的情况下，通过了解独特的方面， 新生儿反应

Project Abstract Late onset sepsis (LOS), a bloodstream infection and a leading cause of death in newly born babies accounting for 26% of all neonatal deaths, represents a major threat to prematurely born infants. Increased hygiene practices have failed to substantially reduce LOS incidence, which has paradoxically increased in the past forty years due to a continual reduction in the age of viability due to increased medical technology to care for prematurely born infants. Currently, LOS is treated with intravenous antibiotics, but antibiotic resistant bacteria are becoming a greater concern. Additionally, LOS patients are a greater risk for long-term cognitive developmental problems. In a substantial portion of LOS, the pathogen can be found as a resident of the neonatal gut microbial community prior to disease, yet an incomplete understanding as to how LOS initially develops and a lack of an animal model to explore the mechanism, treatment and prevention of LOS onset is a barrier to progress in this field. Moreover, an increasing trend of LOS cases caused by members of the normal skin and intestinal flora, compels the exploration of what defines a sepsis-pathogen. However, it remains unclear: 1) how the enteric pathogen disseminates and 2) the subsequent cause of respiratory and organ failure that contributes to death following LOS. It has been assumed the neonatal response is one of immaturity and ignorance that lacks the ability to properly fight bacterial pathogens due to a state of immunosuppression until the immune system fully matures, resulting in the neonate being overwhelmed by systemic bacterial replication and toxin production. I have developed an animal model, whereby disruption of synchronous breast-feeding results in translocation of gut pathogens from the intestine to the system, resulting in sepsis. I will utilize this model to explore the immune response in the neonate, and translate these findings to the human using peripherally derived leukocytes and lymphocytes from infant blood samples. My hypothesis, in contrast to the current view of neonatal immune responses and based on recent clinical findings of a cytokine signature unique to neonates including increased serum IL-6, is that neonates produce a massive cytokine response following systemic bacterial infections. Additionally, human data revealed sepsis pathogens contribute to the non-specific activation of T cells within 4 hours, suggesting the combination of IL-6 and non-specific activation of lymphocytes may result in a cytokine storm the leads to death. This project will utilize animal models, human blood samples, sepsis pathogens, and a variety of flow cytometry-based assays to explore the immune response to sepsis pathogens. Following the completion of this project, I will understand what the response downstream of systemic bacterial infection in neonates is composed of, which will allow for further exploration into how bacterial components unique to sepsis pathogens cause a massive cytokine response. Also, this work will allow for the development of interventions and preventative therapeutics specific for neonatal sepsis cases, by understanding the unique aspects of the neonatal response.