The Vitamin D–antimicrobial Peptide Pathway and Its Role in Protection against Infection

Adrian F Gombart

Disclosures

Future Microbiol. 2009;4(9):1151-1165. 

In This Article

Vitamin D, TB & Other Infectious Diseases

Since the 1840s, both environmental (i.e., sunlight) and dietary sources (cod liver oil, eggs and liver) of vitamin D have been identified as treatments for TB.[37] By the 1930s, vitamin D had been isolated from cod-liver oil and it was possible to begin using pharmacologic doses of vitamin D for treatment.[37] Effective chemotherapeutic treatments decreased the interest in using cod-liver oil, sunlight and vitamin D for TB treatment, but studies over the last two decades have demonstrated that vitamin D deficiency is a risk factor for active TB and impaired antimycobacterial activity.[25,69–71]

The mechanism of immune modulation that boosted antimycobacterial acitivity had remained an enigma. In the mid 1980s, vitamin D was found to boost the antimicrobial activity of human monocytes/macrophages against Mycobacterium tuberculosis.[72] Most recently, we and others discovered that vitamin D strongly upregulated antimicrobial peptide gene expression.[38,39] Subsequently, it was demonstrated in vitro that TLR2/1 signaling by a synthetic 19-kD M. tuberculosis-derived lipopeptide enhances the antimicrobial capacity of monocytes via a vitamin D and VDR-dependent pathway.[25] This involved induction of the CAMP gene and its protein.[25,37,73] In the model proposed, TLR2/1 activation of monocyte/macrophages induces the expression of CYP27B1 (25-hydroxyvitamin D-1α-hydroxylase) which, in turn, leads to production of bioactive 1,25(OH)2D from circulating inactive 25(OH)D.[25] Also, the expression of VDR is increased and in the presence of locally high levels of 1,25(OH)2D it activates the CAMP gene (Figure 3).[25]

Figure 3.

Vitamin D-dependent Toll-like receptor-activation of cathelicidin gene expression. The current model proposes that when a pathogen is detected by its respective TLR, VDR and YP27B1 gene expression are induced. This leads to 1-α-hydroxylation of 25(OH)D, which is taken up from the blood (in a complex with the D-binding protein) and subsequent binding of 1,25(OH)2D to the VDR. The cathelicidin gene is activated and the protein (hCAP18/LL-37) is synthesized for use against the pathogen that has been engulfed in the phagosome of the macrophage.
TLR: Toll-like receptor; VDR: Vitamin D receptor.

While there is growing evidence that vitamin D boosts antimycobacterial immunity in vitro, it is essential to elucidate the mechanism for immune modulation in vivo. In a review of three randomized controlled trials and ten case series in which vitamin D had been given to patients with pulmonary TB, it was concluded that the studies to date were flawed methodologically.[74] Two small, randomized studies have suggested beneficial effects of vitamin D on treatment of TB.[75,76] Also, administration of a single oral dose of vitamin D (2.5 mg) to individuals significantly enhanced the ability of their whole blood to restrict bacillus Calmette–Guérin-lux luminescence in vitro without affecting antigen-stimulated IFN-γ responses.[77] In a larger recent double-blind, randomized, placebo-controlled trial it was found that vitamin D did not improve clinical outcome among patients with TB and no overall effect on mortality in patients with TB was observed.[78] The authors went on to conclude that it is possible that the dose used was insufficient. Indeed, both the placebo and treated groups had similar levels of vitamin D at the start of the trial and at 2 and 8 months after the start of treatment.[78] Further controlled, randomized, clinical trials need to be appropriately powered to detect modest effects and investigators should consider dose escalation, dosing frequency schedule and targeting populations that are severely deficient in vitamin D.[79]

Vitamin D deficiency has been correlated with increased rates of other types of infection. Epidemiological studies demonstrate a link between vitamin D deficiency and increased rates of respiratory infections.[80–83] It has been hypothesized that epidemic influenza may be the result of vitamin D deficiency.[84] Maternal vitamin D deficiency is associated with bacterial vaginosis in the first trimester of pregnancy.[85] Low levels of vitamin D are described in HIV-infected individuals and this may have an impact on the progression of the disease.[86] Consistent with the epidemiological data for respiratory infection, activation of the vitamin D pathway in response to respiratory syncitial virus infection occurs in lung cells via TLR3 signaling, resulting in the induction of the CAMP gene.[87] Deficiency in vitamin D could impair this response by cells in the lung.

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