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

• 批准号: 8631798
• 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
• 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/8631798
• 关键词: 1,25 (OH) vitamin D; 25-hydroxyvitamin D; Address; Adjuvant; Affect; Alveolar; Antigens; Autophagocytosis; Blood; Blood Tests; CD8B1 gene; Cell Differentiation process; Cell physiology; Cells; Cholecalciferol; Clinical; Code; Communicable Diseases; Cytoplasm; Data; Dendritic Cells; Disease; Ergocalciferols; Genes; Growth; Host Defense; Human; Immune; Immune response; Immunologics; In Vitro; Individual; Infection; Instruction; Interferon Type II; 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; Regulation; Role; Serum; Stimulus; Supplementation; T cell response; T-Lymphocyte; Test Result; Testing; Therapeutic Intervention; Toll-Like Receptor 2; Tuberculosis; Vitamin D; Vitamin D3 Receptor; Vitamins; Work; adaptive immunity; antimicrobial; cathelicidin antimicrobial peptide; cost; disorder risk; in vivo; insight; macrophage; microbial; monocyte; prohormone; public health relevance; receptor; resistant strain; response; single cell analysis

Project Summary / Abstract 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.

项目摘要 /摘要 该提案的长期目标是了解先天和先天性的维生素D依赖机制 人类的适应性免疫学。我们以前的工作揭示了一种新的免疫学范式 强调了足够循环25-羟基维生素D（25D）水平的人类宿主防御的重要性 反对微生物感染。我们证明了在人类巨噬细胞中：先天和适应性机制 激活不同的受体，但会收敛于常见的维生素D受体（VDR）驱动的抗菌途径 针对结核分枝杆菌（MTB），涉及IL-15和维生素D-1 - 羟化酶的诱导 （CYP27B1），将25D转换为活性代谢产物1,25-二羟基维生素D（1,25D）。随后的 VDR的激活诱导了编码抗菌胡椒的下游基因，Cathelicidin和defb4， 加上自噬，导致抗菌活性。令人惊讶的是，这种抗菌途径是 取决于25D的水平，这也与人类结核病的易感性相关。我们的中心 假设是，有效的先天和适应性需要足够的25D循环水平 对MTB的免疫反应，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依赖性抗菌途径中的独特和互动作用，2） 通过I型IFN调查抗菌活性的反调节； 3）确定25D的影响 树突电池（DC）功能的可用性。拟议的研究将提供有关 人类先天和适应性免疫的机制，与结核病具有特定的相关性，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的辅助 传染病。