The Role of Vitamin D and Vitamin D Receptor in Immunity toLeishmania majorInfection

Abstract

Vitamin D signaling modulates a variety of immune responses. Here, we assessed the role of vitamin D in immunity to experimental leishmaniasis infection in vitamin D receptor-deficient mice (VDRKO). We observed that VDRKO mice on a genetically resistant background have decreased Leishmania major-induced lesion development compared to wild-type (WT) mice; additionally, parasite loads in infected dermis were significantly lower at the height of infection. Enzymatic depletion of the active form of vitamin D mimics the ablation of VDR resulting in an increased resistance to L. major. Conversely, VDRKO or vitamin D-deficient mice on the susceptible Th2-biased background had no change in susceptibility. These studies indicate vitamin D deficiency, either through the ablation of VDR or elimination of its ligand, 1,25D3, leads to an increase resistance to L. major infection but only in a host that is predisposed for Th-1 immune responses.

A Transcriptomic Network Identified in Uninfected Macrophages Responding to Inflammation Controls Intracellular Pathogen Survival

“…For example, changes in components of the sterol biosynthesis pathway were induced by macrophage infection with L. amazonensis ( Osorio y Fortéa et al., 2009 ). Previous studies have characterized a role for two heterodimeric partners of RXR in the control of Leishmania major infection, the vitamin D receptor (VDR) ( Ehrchen et al., 2007; Whitcomb et al., 2012 ) and the liver X receptor (LXR) ( Bruhn et al., 2010 ), with deficiency in either receptor resulting in enhanced resistance to infection. In addition, upregulation of VDR was previously reported following in vitro infection of macrophages with L. chagasi ( Rodriguez et al., 2004 ) as well as L. donovani and L. major ( Chaussabel et al., 2003 ), suggesting that VDR is an important component of the host response to Leishmania infection.…”

The vitamin D receptor turns off chronically activated T cells

“…Paradoxically, 1,25(OH) 2 D 3 treatment of mice at doses that inhibit T H 1 and T H 17 cell responses in immune‐mediated disease had no effect on the ability of the host to clear a yeast or viral infection . In addition, VDR KO mice were able to clear bacterial and parasitic infections with kinetics that were not that different from WT mice . The ability of vitamin D and 1,25(OH) 2 D 3 to suppress T H 1 and T H 17 in immune‐mediated diseases but not in infectious diseases is paradoxical.…”

“…42 In addition, VDR KO mice were able to clear bacterial and parasitic infections with kinetics that were not that different from WT mice. 43,44 The ability of vitamin D and 1,25(OH) 2 D 3 to suppress T H 1 and T H 17 in immune-mediated diseases but not in infectious diseases is paradoxical.…”

Vitamin D Every Day to Keep the Infection Away?

“…However, in vitro investigations of different mouse models, including VDR KO mice, 1,25D-treated wild type (WT) mice, vitamin D deficient or sufficient WT mice, reveal conflicting results. VDR KO mice infected with the intracellular pathogen L. major indeed showed smaller lesions and lower parasite burden, which was related to decreased nitric oxide and an increased arginase-1 expression [ 94 , 95 ]. However, the CD4 + and CD8 + Th1 responses were not altered in these mice.…”