Evaluating the role of cytomegalovirus and age on lung immune homeostasis and responses to respiratory infections

摘要/项目总结 免疫系统对于防止感染、癌症、过敏和自身免疫是重要的。 个体间在产生有效免疫应答的能力上存在显著差异， 是由遗传和环境因素共同驱动的。有证据表明， 免疫稳态可能影响对攻击的免疫应答。然而， 涉及的特定基因和作用机制在很大程度上是未知的。此外，相互作用 环境压力、遗传变异和衰老之间的关系在很大程度上还没有得到充分研究。长期 本研究的目的是了解遗传和环境机制如何调节免疫 稳态，这种调节如何随年龄变化，以及这些因素如何有助于免疫 对感染的反应。我们的实验室先前已经表明，遗传多样性在很大程度上有助于 免疫反应的变化。此外，我们已经证明，这可以通过改变 自我平衡的免疫环境在这里，我们提出甲基CpG结合域蛋白1， （MBD 1）是稳态时效应B细胞分化的调节剂（Aim 1）。为此，我们力求 阐明MBD 1调节B细胞分化的机制，并评估等位基因 Mbd 1的变异改变了其在体外和体内的功能。大多数免疫稳态研究 在无特定病原体的小鼠模型中进行，其免疫系统在很大程度上反映了 一个新生儿为了在免疫稳态的背景下解决这一问题，我们将研究 巨细胞病毒（CMV）和年龄对肺部免疫环境的影响。这里我们 询问是否与肺部免疫环境的老化相关变化被CMV修饰 感染、潜伏期和/或再激活。此外，我们将研究这些变化是否有助于 改善老年小鼠对呼吸道感染的免疫应答（目的2）。数据生成通过 这一提议将为免疫稳态如何随着遗传变异而改变提供新的线索， 免疫暴露和年龄，并将提高我们对这些因素在 对感染的反应。

ABSTRACT/PROJECT SUMMARY The immune system is important for protection against infection, cancers, allergy, and autoimmunity. There is significant interindividual variation in the ability to mount an effective immune response that is driven by both genetic and environmental factors. Evidence shows that underlying variation in immune homeostasis may influence the immune response to challenge. However, the identity of specific genes involved, and mechanism of action are largely unknown. Additionally, the interplay between environmental stressors, genetic variation, and aging is largely understudied. The long-term goal of this study is to understand how genetic and environmental mechanisms regulate immune homeostasis, how this regulation changes with age, and how those factors contribute to the immune response to infection. Our lab has previously shown that genetic diversity substantially contributes to variation in immune responses. Further, we’ve shown that this could be mediated through changes in the homeostatic immune environment. Here, we propose that Methyl-CpG binding domain protein 1 (MBD1) is a regulator of effector B cell differentiation at homeostasis (Aim 1). In this aim we seek to elucidate the mechanism by which MBD1 regulates B cell differentiation and assess how allelic variation at Mbd1 alters its functions both in vitro and in vivo. Most studies of immune homeostasis are performed in specific-pathogen free mouse models, whose immune systems largely reflect that of a neonatal human. To address this in the context of immune homeostasis, we will examine the contributions of cytomegalovirus (CMV) and age to the immune environment in the lungs. Here, we ask whether aging associated changes in the immune environment in the lungs is modified with CMV infection, latency, and/or reactivation. Further, we will investigate whether these changes contribute to improved immune responses to respiratory infections in aged mice (Aim 2). Data generated through this proposal will shed new light on how immune homeostasis is modified with genetic variation, prior immune exposure, and age, and will improve our understanding of the role that these factors play in response to infection.