Vitamin D Metabolism in Leprosy

维生素D在麻风分枝杆菌(MLEP)的发病和治疗中的作用已被推测 多年来。患有进行性、富含杆菌的麻风型(L-LEP)的患者 疾病更有可能是维生素D缺乏，临床上受益于紫外线B(阳光)辐射 或者饮食中补充维生素D。这样的孩子也有患上过度营养不良的风险。 维生素D代谢产物1，25-二羟基维生素D(1，25D)的生产 由疾病激活的巨噬细胞产生的羟基维生素D(25D)。另一方面，细胞内1，25D合成 维生素D受体(VDR)水平上的Acfion对于建立抗菌反应至关重要 MLEP。因此，控制麻风维生素D代谢和活性的机制(S)是关键 与疾病有关的成分。我们最近的体外研究清楚地证明了不同的表达 维生素D系统的功能元件，包括CYP27B1-羟基酶和I型和II型维生素D受体 干扰素驱动、T淋巴细胞和L淋巴肉芽肿。总而言之，这些临床和实验室 这些发现使我们推测mLEP感染和相应的T-Lep或L-Lep下游干扰素- 定向途径，将不同地影响活性维生素D的合成、代谢和功能 巨噬细胞中的代谢产物和其他激发的、VDR表达的炎性细胞在感染性 麻风宿主的微环境。为了验证这一假设，我们将从概念上进行三个方面的研究 新颖、机械化的目标。首先，维生素D系统的组成成分(细胞色素P450受体1、维生素D羟基酶； 在T-LEP和L-LEP中进行了定量定位 单细胞水平的肉芽肿。第二，T-LEP或L-LEP免疫反应的协同效应 分泌体和相关的下游干扰素反应对新陈代谢和免疫激活的影响 人类炎性细胞中的维生素D将使用创新的五种分子工具进行表征 项目1和3。第三，使用最近构思的RNA测序技术，功能 人类宿主维生素D缺乏状态的后果及其体内外拯救对免疫的影响 将探讨对mLEP的反应和对其的杀伤。当分析与实验结果相一致时 其他CORT项目，相信这项工作将为操作的实践奠定基础 人类维生素D平衡在促进麻风先天和获得性免疫反应中的特异性 在肉芽肿形成的疾病中也是如此。

A role for vitamin D in the pathogenesis and treatment of Mycobacterium leprae (mLEP) has been presumed for many years. Pafients suffering from the progressive, bacilli-abundant lepromatous form (L-lep) ofthe disease are more likely to be vitamin D-deficient and benefit clinically from ultraviolet B (sunlight) irradiafion or dietary supplementafion vitamin D. Such pafients are also at risk for developing dysregulated over- producfion of the acfive vitamin D metabolite 1,25-dihydroxyvitamin D (1,25D) from circulafing 25- hydroxyvitamin D (25D) by disease-activated macrophages. On the other hand, intracellular 1,25D synthesis and acfion at the level of the vitamin D receptor (VDR) is crucial for mounfing an anfimicrobial response to mLEP. Therefore, the mechanism(s) that govern vitamin D metabolism and acfion in leprosy is a key component to the disease. Our recent studies In vitro clearly demonstrate the differenfial expression of the funcfional elements ofthe vitamin D system, including CYP27B1-hydroxylase and the VDR in Type I and II interferon-driven, T-lep and L-lep granulomas, respecfively. Taken together, these clinical and laboratory findings lead us to theorize that mLEP Infection and the respective T-lep or L-lep downstream interferon- directed pathways, will differentially Impact the synthesis, metabolism and function of active vitamin D metabolites in the macrophage and other elicited, VDR-expressing inflammatory cells in the infectious microenvironment ofthe host with leprosy. To test this hypothesis, we will undertake three conceptually novel, mechanisfic aims. First, the vitamin D system components (CYP2R1, vitamin D hydroxylase; CYP27B1; CYP24A1, 24-hydroxylase; and VDR) will be quantitafively mapped in T-lep and L-lep granulomas at the single cell level. Second, the orchestrated effects of T-lep or L-lep immune response secretomes, and associated downstream interferon responses, on the metabolism and immunoacfion of vitamin D in human inflammatory cells will be characterized using innovafive molecular tools developed in Projects 1 and 3. Third, using recently-conceived RNA sequencing technologies, the funcfional consequences ofthe human host vitamin D deficient state, and its rescue In vitro and in vivo, on immune responses to and killing of mLEP will be probed. When analyzed in concert with the experimental results of the other CORT projects, it is anficipated that this work will set the stage for the pracfice of manipulating human vitamin D balance in promofion ofthe innate and adapfive immune response in leprosy specifically and in granuloma-forming diseases in general.