Evaluating the role of cytomegalovirus and age on lung immune homeostaasis and response to respiratory infections

评估巨细胞病毒和年龄对肺免疫稳态和呼吸道感染反应的作用

• 批准号: 10832913
• 负责人: Brea Hampton Brown
• 金额: $ 7.54万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-05 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10832913
• 关键词: Address; Age; Aging; Alleles; Animals; Antibodies; Architecture; Autoimmunity; B cell differentiation; B-Lymphocyte Subsets; B-Lymphocytes; Bacterial Infections; CD19 gene; Candidate Disease Gene; Cells; Chromatin; Chromosome 18; Chronic; Cytomegalovirus; Cytomegalovirus Infections; Data; Effector Cell; Elderly; Environment; Environmental Exposure; Environmental Risk Factor; Gene Expression; Genes; Genetic; Genetic Variation; Genome; Genotype; Goals; Haplotypes; Herpesviridae; Homeostasis; Hypersensitivity; IgG1; Immune; Immune response; Immune system; Immunity; Immunoglobulin D; Immunoglobulin M; Immunoglobulin-Secreting Cells; In Vitro; Infection; Inflammation; Lung; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Morbidity - disease rate; Mus; Organ; Phenotype; Play; Postdoctoral Fellow; Protein Binding Domain; Quantitative Trait Loci; Readiness; Regulation; Research; Research Personnel; Resistance; Respiratory Tract Infections; Role; Secondary to; Serum; Site; Spleen; T-cell receptor repertoire; Tissues; Vaccination; Variant; Work; aged; cohort; data integration; environmental stressor; gene network; genetic variant; germ free condition; immunoregulation; immunosenescence; improved; in vivo; insight; inter-individual variation; interest; mortality; mouse model; neonatal human; programs; protein function; protein protein interaction; respiratory pathogen; response; secondary infection

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.

摘要/项目摘要 免疫系统对于保护感染，癌症，过敏和自身免疫性很重要。 实现有效免疫反应的能力的个人间个体差异是显着的 由遗传因素和环境因素驱动。 免疫稳态可能会影响挑战的免疫反应。 涉及的特定基因和作用机制是未知的 在环境压力源，遗传变异和衰老之间进行了更大的研究 这项研究的目标是了解遗传和环境机制如何调节免疫 稳态，该调节如何随着年龄的变化而变化，以及这些因素如何促进免疫 对感染的反应。 免疫反应的变化。 稳态免疫环境。 （MBD1）是稳态的效应B细胞分化的调节剂（AIM 1）。 阐明MBD1定于B细胞分化的机制并评估等位基因 MBD1的变化在体外和体内都可以变化。 在特定的无病因小鼠模型中进行，其IMUNE系统在很大程度上反映了反射。 新生儿的人类在免疫稳态的情况下解决这个问题 胞瘤病毒（CMV）和年龄对肺部免疫环境的贡献。 询问是否使用CMV修饰肺部免疫环境的相关变化 感染，潜伏期和/或重新激活。 改善了老年小鼠呼吸道感染的免疫反应（AIM 2） 该提案带有新的启示，了解如何通过遗传变异来改变imeostasis，以前 免疫暴露和年龄，并将提高我们对这些因素的理解 对感染的反应。