EPIGENETIC PROGRAMMING OF INNATE IMMUNITY IN PEDIATRIC AIRWAY EPITHELIUM

 描述(申请人提供)：人类生命的第一年是肺部和免疫系统的重要成熟期。与学龄儿童和成人相比，婴儿更容易受到呼吸道感染，但这一临床观察的免疫机制尚不清楚。由于疫苗效力下降，新生儿的生命周期受到进一步挑战，这部分是由于白细胞功能的发育变化限制了保护性免疫的建立。目前尚不清楚细胞的结构是否 肺也有助于婴儿的免疫功能受损状态。特别相关的是上皮细胞在传导呼吸道中的作用，它在结构上和功能上都是有毒的，是作为适应性免疫系统的先天免疫联系人。鉴于粘膜表面是宿主防御的第一道防线，增强呼吸道上皮的天然免疫功能可能有助于对感染性病原体做出更强大的适应性免疫反应。我们研究的总体目标是了解在出生后肺的呼吸道上皮细胞中编程先天免疫功能的分子机制。在H1N1流感感染的儿科模型中，我们观察到婴儿恒河猴呼吸道持续的毛细支气管炎和肺泡炎，尽管病毒清除了。与成年猴呼吸道上皮细胞培养相比，H1N1感染后的幼猴呼吸道上皮细胞培养显示出一种受调节的天然免疫表型。我们现在提供的数据表明，白介素22受体α1(IL-22R1)是以组蛋白脱乙酰酶依赖的方式在幼猴呼吸道上皮细胞中进行发育调节的。考虑到我们已发表的和初步的发现，我们假设婴儿有限的宿主病原体防御在一定程度上是通过调节呼吸道上皮中的天然免疫途径来调节的。我们进一步提出，调节婴儿呼吸道上皮细胞的天然免疫通路依赖于表观遗传机制。为了验证我们的假设，我们将在H1N1感染的背景下使用体外和体内策略来(1)确定病毒感染背景下婴儿呼吸道上皮相对于成人呼吸道上皮的转录组的连续体；(2)研究调节婴儿呼吸道上皮中IL-22R1的表观遗传机制；(3)确定表观遗传抑制物是否可以增强婴儿呼吸道的粘膜免疫。在R21机制下提出这些探索性研究的基本原理是，通过靶向与先天免疫通路相关的特定分子，为开发针对儿科呼吸道上皮的宿主防御新的佐剂策略提供基础。虽然人们知道呼吸道上皮细胞有多个模式识别受体来识别各种病原体，但在这里，我们将重点放在流感作为呼吸道感染的一个范例上。

 DESCRIPTION (provided by applicant): The first year of human life is a period of significant maturation for both the lung and immune system. Infants are more susceptible to respiratory infections as compared to school age children and adults, but the immune mechanisms for this clinical observation are not well understood. The neonatal period of life is further challenged by reduced vaccine efficacy, which is in part due to developmental shifts in leukocyte function that limit establishment of protective immunity. It is currently unknown whether structural cells of the lung also contribute to the immunocompromised state of the infant. Of particular relevance is the role of the epithelial cell in conducting airways, which is architecturally and functionally poisedto serve as an innate immune liaison to the adaptive immune system. Given that mucosal surfaces serve as the first line of host defense, enhancement of innate immune function in airway epithelium may facilitate a more robust adaptive immune response towards infectious agents. The overall goal of our research is to understand the molecular mechanisms that program innate immune function in airway epithelial cells of the postnatal lung. In a pediatric model of H1N1 influenza infection, we have observed persistent bronchiolitis and alveolitis in infant rhesus monkey airways despite viral clearance. Infant monkey airway epithelial cell cultures revealed a modulated innate immune phenotype following H1N1 infection, as compared with adult monkey airway epithelial cell cultures. We now provide data demonstrating that interleukin 22 receptor, alpha 1 (IL-22R1), is developmentally regulated in infant monkey airway epithelial cells in a histone deacetylase dependent fashion. Given our published and preliminary findings, we hypothesize that limited host pathogen defense in the infant is mediated, in part, by modulated innate immune pathways in the airway epithelium. We further propose that the regulation of modulated innate immune pathways in infant airway epithelium is dependent upon epigenetic mechanisms. To test our hypothesis, we will use both in vitro and in vivo strategies in the context of H1N1 infection to (1) define the continuum of the infant airway epithelium transcriptome relative to adult airway epithelium in the context of viral infection; (2) investigat the epigenetic mechanisms that regulate IL-22R1 in the infant airway epithelium; (3) determine if epigenetic inhibitors can enhance mucosal immunity in infant airways. The rationale for proposing these exploratory studies under the R21 mechanism is to provide the foundation for the development of new adjuvant strategies for host defense directed at pediatric airway epithelium, by targeting specific molecules associated with innate immune pathways. While it is understood that airway epithelium has multiple pattern recognition receptors to recognize a diverse array of pathogens, here we will focus on influenza as a paradigm for respiratory infections.