EPIGENETIC PROGRAMMING OF INNATE IMMUNITY IN PEDIATRIC AIRWAY EPITHELIUM

 描述（由申请人提供）：人类生命的第一年是肺和免疫系统显著成熟的时期。与学龄儿童和成人相比，婴儿更容易患呼吸道感染，但这种临床观察的免疫机制尚不清楚。新生儿期的生命受到疫苗效力降低的进一步挑战，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。目前尚不清楚是否结构细胞的 肺也有助于婴儿的免疫功能低下状态。特别相关的是上皮细胞在传导气道中的作用，其在结构上和功能上被定位为充当与适应性免疫系统的先天免疫联络。考虑到粘膜表面作为宿主防御的第一道防线，气道上皮中先天免疫功能的增强可促进对感染因子的更稳健的适应性免疫应答。我们研究的总体目标是了解在出生后肺的气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，我们观察到尽管病毒清除了，但婴儿恒河猴气道中仍存在持续性细支气管炎和肺泡炎。与成年猴气道上皮细胞培养物相比，婴儿猴气道上皮细胞培养物揭示了H1N1感染后调制的先天免疫表型。我们现在提供的数据表明，白细胞介素22受体，α 1（IL-22 R1），是发育调节的婴儿猴气道上皮细胞中的组蛋白脱乙酰酶依赖的方式。鉴于我们已发表的初步研究结果，我们假设婴儿中有限的宿主病原体防御部分是由气道上皮中调制的先天免疫途径介导的。我们进一步提出，在婴儿气道上皮调制的先天免疫途径的调节是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气道上皮相对于成人气道上皮的连续体转录组;（2）研究调节婴儿气道上皮中IL-22 R1的表观遗传机制;（3）确定表观遗传抑制剂是否可以增强婴儿气道中的粘膜免疫。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途径相关的特异性分子，为开发针对儿科气道上皮的宿主防御新佐剂策略提供基础。虽然气道上皮细胞具有多种模式识别受体来识别各种病原体，但在此我们将重点关注流感作为呼吸道感染的范例。

 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.