Grant: Operating Grant

Tuberculosis (TB) has been resurgent, with approx. 9 million cases and 1.7 million deaths in 2004, and represents the leading cause of death from a curable disease. M. tuberculosis has evolved to replicate within macrophages - the cells designed to kill it. Macrophages are sites of vitamin D action, and there is broad evidence that vitamin D modulates macrophage responses to TB. Vitamin D was discovered as the curative agent of nutritional rickets, which arises from insufficient uptake of dietary calcium. Work in the 1820's showed that cod liver oil or sunbathing cured rickets. Indeed, vitamin D can be produced by moderate exposure of skin to solar ultraviolet B radiation. Notably, cod liver oil was used to treat TB in 1849, and Niels Finsen won the 1903 Nobel Prize for showing that UVB could be used to treat cutaneous TB. As a result of sun avoidance and inadequate dietary intake, vitamin D insufficiency or deficiency is widespread, and elevated levels of TB, particularly in vulnerable immigrant populations, have long been associated with vitamin D deficiency. Vitamin D is converted to 1,25-dihydroxyvitamin D, the active form. 1,25D binds to the nuclear vitamin D receptor (VDR), which functions as a ligand-stimulated regulator of gene transcription. Altering the transcription of specific genes ultimately leads to changes in protein content and function of cells. Our previous genomics work led to the discovery that 1,25D directly stimulates antimicrobial innate immunity through its effects on specific gene transcription. We hypothesize that 1,25D acts to stimulate innate immune responses to TB and regulates pathways leading to infected cell death. Our preliminary data for this application suggest that 1,25D acts to create a more hostile environment within both infected cells and adjacent tissue. The application is composed of 4 aims designed to extend this data to understand the genomic and molecular events that underlie the antibacterial activity of vitamin D.