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.
When analyzed in concert with the experimental results of the other CORT projects, it is our expectafion that the experimental plan set forth here will accomplish two goals. First, this work will describe condifions for vitamin D supplementafion in populafions where leprosy and vitamin D deficiency co-exist. Second, these results will set the stage for the pracfice of manipulafing human vitamin D balance in promofion of the immune response in leprosy and other inflammatory diseases of the skin.
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