Role of Vitamin D Prohormone 25-OHD in the Immune Response to Tuberculosis

维生素 D 激素原 25-OHD 在结核病免疫反应中的作用

基本信息

批准号：
9297106
负责人：
Philip T. Liu
金额：
$ 38.32万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9297106
关键词：
25-hydroxyvitamin D Address Adjuvant Affect Alveolar Antigens Autophagocytosis Blood Blood Tests CD8-Positive T-Lymphocytes CYP27B1 gene Cell Differentiation process Cell physiology Cells Cholecalciferol Clinical Code Communicable Diseases Cytoplasm Data Dendritic Cells Dihydroxycholecalciferols Disease Ergocalciferols Genes Growth Host Defense Human Ii-Key Immune Immune response Immunologics In Vitro Individual Infection Instruction Interferon Type II Interferon-beta Interferons Interleukin-10 Interleukin-15 Ligands MHC Class I Genes Measures Mixed Function Oxygenases Modeling Multi-Drug Resistance Mycobacterium tuberculosis Natural Immunity Pathway interactions Patients Predisposition Prevention Prevention therapy Process Role Serum Stimulus T cell response TLR2 gene Test Result Testing Therapeutic Intervention Tuberculosis Vitamin D Vitamin D supplementation Vitamin D3 Receptor Vitamins Work adaptive immune response adaptive immunity antimicrobial cathelicidin antimicrobial peptide cost counterregulation disorder risk ds-DNA immunoregulation in vivo insight macrophage microbial monocyte permissiveness prohormone public health relevance receptor resistant strain response single cell analysis

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to gain insight into vitamin D-dependent mechanisms of innate and adaptive immunity in humans. Our previous work has revealed a new immunologic paradigm which underscores the importance of adequate circulating 25-hydroxyvitamin D (25D) levels for human host defense against microbial infection. We demonstrated that in human macrophages: innate and adaptive mechanisms activate different receptors but converge on a common vitamin D receptor (VDR)-driven antimicrobial pathway against M. tuberculosis (mTB) involving the induction of IL-15 and the the vitamin D-1�-hydroxylase (CYP27b1), which converts 25D to the active metabolite 1,25-dihydroxyvitamin D (1,25D). Subsequent activation of the VDR induces downstream genes coding for the antimicrobial peptides cathelicidin and DEFB4, together with induction of autophagy, result in antimicrobial activity. Strikingly, this antimicrobial pathway was dependent on levels of 25D, which also correlate with susceptibility to tuberculosis in humans. Our central hypothesis is that adequate circulating 25D levels are critically required for effective innate and adaptive immune responses against mTB, which we will test according to the following specific aims: 1) define the distinct and interactive roles of IL-15 and IL-32 in the induction of the 25D-dependent antimicrobial pathway, 2) investigate counter-regulation of antimicrobial activity by Type I IFNs; and 3) determine the effects of 25D availability on dendritic cell (DC) function. The proposed studies will provide new information about the mechanisms of human innate and adaptive immunity with specific relevance to TB but of significance to the potential use of simple, inexpensive vitamin D supplementation as an adjunct to prevention and therapy of infectious disease.

描述（由适用提供）：该提案的长期目标是了解人类先天和适应性免疫学的维生素D依赖机制。我们以前的工作揭示了一种新的免疫范式，强调了足够的25-羟基维生素D（25D）水平的足够循环的人类宿主防御微生物感染的重要性。 We demonstrated that in human macrophages: innate and adaptive mechanisms activate Different receptors but converge on a common vitamin D receptor (VDR)-driven antimicrobial pathway against M. tuberculosis (mTB) involving the induction of IL-15 and the vitamin D-1�-hydroxylase (CYP27b1), which converts 25D to the active metabolite 1,25-二羟基维生素D（1,25d）。随后的VDR激活诱导编码抗菌胡椒的cathelicidin和defb4的下游基因，并诱导自噬，从而导致抗菌活性。令人惊讶的是，这种抗菌途径取决于25D的水平，这也与人类结核病的易感性相关。我们的核心假设是，有效的先天和针对MTB的自适应免疫调查，我们将根据以下特定目的进行测试：1）定义IL-15和IL-32在诱导25d依赖性抗菌途径的诱导中的独特和相互作用，2）2）研究通过I型IFN研究抗菌活性的反应； 3）确定25D可用性对树突状细胞（DC）功能的影响。拟议的研究将提供有关人类先天和适应性免疫机制的新信息，并具有与结核病的特定相关性，但对潜在使用简单，廉价的维生素D补充剂作为预防和治疗感染疾病的辅助作用具有重要意义。