IMPACT OF FARMING ENVIRONMENT ON IMMUNE MATURATION AND RESPIRATORY HEALTH

项目概述（见说明）：本提案的主要目标是更好地了解免疫成熟及其与病毒性呼吸道感染疾病严重程度的关系。病毒性呼吸道感染（VRI）是婴儿的重大健康风险。这些常见的儿童感染缺乏治疗方法或有效的疫苗，在生命的头5年导致大量发病率和死亡率。因此，自愿生殖病毒感染是一个重大的公共卫生问题，影响到受影响儿童的生活质量，并增加了工作场所和医疗保健利用方面的社会压力。此外，vri似乎具有长期持久的健康影响，例如在一些儿童中导致慢性过敏性疾病的发展。独特的是，来自MESA未发表的数据表明，与非农场儿童相比，农场儿童在出生后头2年的呼吸道感染显著减少。这些影响与世界各地发表的研究结果相吻合，即接触农场可以降低儿童过敏和哮喘的风险。值得注意的是，过敏原致敏的发展和对VRIs的最高易感性与免疫系统的成熟阶段一致，有证据表明，农场暴露增强了先天免疫和T调节（Treg）细胞功能的发展。我们假设农场暴露通过增强先天抗病毒免疫和Treg功能的发展来降低幼儿患vri的风险。为了验证这一假设，我们将从MESA内的威斯康星州农场和非农业家庭中开展一项独特的出生队列研究。定义先天和Treg细胞成熟的功能测定将以纵向方式与vri和过敏致敏性监测一起使用。更好地了解环境暴露如何通过对免疫成熟的影响促进对vri的抗性并减少过敏性疾病，将有助于制定新的战略，使生活在其他地方的人受益于农场暴露。除了解决这些研究目标外，该项目还将作为广泛表征临床标本（气道上皮细胞，鼻病毒临床分离物）的来源，这将使机制研究能够确定导致临床疾病严重程度的宿主-病毒相互作用。

PROJECT SUMMARY (See instructions): The major goal of this proposal is to better understand immune maturation and its relationship to viral respiratory infection disease severity. Viral respiratory infections (VRI) are a significant health risk to infants. These common childhood infections, for which few therapeutics or effective vaccines exist, result in significant morbidity and mortality during the first 5 years of life. As such, VRIs are a significant public health problem impacting the quality of life of affected children and places increased societal strain in the workplace and on health care utilization. Additionally VRIs appear to have a long lasting health impact, for example in some children resulting in the development of chronic allergic diseases. Uniquely, unpublished data from MESA demonstrate significantly decreased respiratory infections during the first 2 years of life in farm children compared to non-farm children. These effects parallel published findings from around the world that farm exposures lower the risk of childhood allergies and asthma. Notably, the development of allergen sensitization and highest vulnerability to VRIs coincides with the maturation phase of the immune system, and there is evidence that farm exposures enhance development of innate immunity and T regulatory (Treg) cell function. We hypothesize that farm exposures reduce the risk of VRIs in young children by enhancing the development of innate antiviral immunity and Treg function. To test this hypothesis, we will develop a unique birth cohort study from Wisconsin farm and non-farm families within MESA. Functional assays to define innate and Treg cell maturation will be utilized in a longitudinal manner along with surveillance of VRIs and allergic sensitization. A better mechanistic understanding of how environmental exposures promote resistance to VRIs and diminish allergic diseases through effects on immune maturation will allow for development of new strategies to bring benefits of farm exposures to those who live elsewhere. In addition to addressing these research goals, this project will serve as a source of extensively characterized clinical specimens (airway epithelial cells, clinical isolates of rhinoviruses) that will enable mechanistic studies to define host-virus interactions that contribute to the severity of clinical illnesses.