IMPACT OF FARMING ENVIRONMENT ON IMMUNE MATURATION AND RESPIRATORY HEALTH

项目摘要(见说明)：这项建议的主要目标是更好地了解免疫成熟及其与病毒呼吸道感染疾病严重程度的关系。病毒性呼吸道感染(VRI)对婴儿的健康构成重大威胁。这些常见的儿童感染几乎没有治疗方法或有效的疫苗，在生命的头5年会导致严重的发病率和死亡率。因此，VRIs是一个严重的公共卫生问题，影响受影响儿童和场所的生活质量，增加了工作场所的社会压力和卫生保健利用。此外，VRI似乎对健康有长期的影响，例如在一些儿童中会导致慢性过敏性疾病的发展。独一无二的是，来自MESA的未发表数据显示，与非农业儿童相比，农场儿童在出生后头两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平行，即农场暴露降低了儿童过敏和哮喘的风险。值得注意的是，过敏原敏感性和对VRIs的最高易感性的发展与免疫系统的成熟阶段相吻合，并且有证据表明，农场暴露促进了先天免疫和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VRI的风险。为了验证这一假设，我们将对梅萨地区威斯康星州农场和非农场家庭进行一项独特的出生队列研究。将以纵向方式利用功能分析来确定先天和Treg细胞成熟情况，同时监测VRIs和过敏反应。更好地从机制上理解环境暴露如何提高对VRI的抵抗力，并通过影响免疫成熟来减少过敏性疾病，将有助于开发新的战略，将农场暴露的好处带给生活在其他地方的人。除了解决这些研究目标外，该项目还将作为具有广泛特征的临床标本(呼吸道上皮细胞、鼻病毒临床分离株)的来源，使机械性研究能够确定有助于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 Uniquely, unpublished data from MESA demonstrate significantly decreased respiratory infections during the first 2 years of life in farm children compared to non-farm children.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.