Abstract
Although vitamin D deficiency is a common feature among patients presenting with active tuberculosis, the full scope of vitamin D action during Mycobacterium tuberculosis (Mtb) infection is poorly understood. As macrophages are the primary site of Mtb infection and are sites of vitamin D signaling, we have used these cells to understand the molecular mechanisms underlying modulation of the immune response by the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D). We found that the virulent Mtb strain H37Rv elicits a broad host transcriptional response. Transcriptome profiling also revealed that the profile of target genes regulated by 1,25D is substantially altered by infection, and that 1,25D generally boosts infection-stimulated cytokine/chemokine responses. We further focused on the role of 1,25D- and infection-induced interleukin 1β (IL-1β) expression in response to infection. 1,25D enhanced IL-1β expression via a direct transcriptional mechanism. Secretion of IL-1β from infected cells required the NLRP3/caspase-1 inflammasome. The impact of IL-1β production was investigated in a novel model wherein infected macrophages were co-cultured with primary human small airway epithelial cells. Co-culture significantly prolonged survival of infected macrophages, and 1,25D/infection-induced IL-1β secretion from macrophages reduced mycobacterial burden by stimulating the anti-mycobacterial capacity of co-cultured lung epithelial cells. These effects were independent of 1,25D-stimulated autophagy in macrophages but dependent upon epithelial IL1R1 signaling and IL-1β-driven epithelial production of the antimicrobial peptide DEFB4/HBD2. These data provide evidence that the anti-microbial actions of vitamin D extend beyond the macrophage by modulating paracrine signaling, reinforcing its role in innate immune regulation in humans.
Highlights
Mycobacterium tuberculosis (Mtb) infects,2 billion people [1] and active tuberculosis (TB) represents the leading cause of death from a curable disease [2]
Elevated levels of TB have long been associated with vitamin D deficiency, strongly suggesting that vitamin D supplementation may be of therapeutic benefit
In this study we profile the host macrophage response to Mtb infection through the use of high-throughput genomics techniques. From this we have discovered that the dominant function of vitamin D is the modulation of the levels of specific cytokines, mediators of immune cell to cell signaling
Summary
Mycobacterium tuberculosis (Mtb) infects ,2 billion people [1] and active tuberculosis (TB) represents the leading cause of death from a curable disease [2]. Innate immunity to Mtb infection is critical for determining disease outcome, and it has long been recognized that during TB outbreak investigations, only 30–50% of those with an equivalent exposure develop a productive infection, as demonstrated by a tuberculin skin-test conversion [3]. Lung epithelial cells are generally not considered part of the innate immune responses to Mtb infection. They represent both a physical and an immunological barrier to infection by contributing to the maintenance of mucosal integrity, promoting phagocytosis, and producing several antimicrobial peptides, vanguards of innate immune responses to infection [4,5]. It has been shown to have direct antimicrobial activity against Mtb and drug-resistant Mtb [7]
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