The Role of Vitamin D and Vitamin D Receptor in Immunity to Leishmania major Infection

Leishmania is a genus of intracellular parasites that are responsible for causing the disease leishmaniasis. Leishmaniasis is a complex of diseases ranging from self-healing cutaneous lesions to fatal visceral disease. Leishmania major is one of several species which causes cutaneous leishmaniasis and is frequently used in immunological research due to the requirement for a T helper 1 (Th-1) mediated response in order for healing and immunity to occur. Vitamin D has been shown to reduce or eliminate many symptoms of T cell mediated autoimmune diseases in experimental mouse models of diseases such as multiple sclerosis, inflammatory bowel disorder, and rheumatoid arthritis. These diseases arise due to an inappropriate Th-1 response to self antigens. The active metabolite of 1,25D3 exerts these actions via interaction with the vitamin D receptor (VDR). These studies aimed to investigate if ablation of the vitamin D receptor or vitamin D deficiency plays a role in influencing Th-1 and Th-2 cytokine balance. We observed that VDR knockout (KO) mice develop smaller lesions in response to L. major infection than their wild type (WT) counterparts. Additionally, VDR KO mice exhibit a decreased parasite burden at the height of infection. We detected increased levels of neutrophils at the site of infection early during infection and elevated numbers of macrophages at the height of infection. In response to vitamin D deficiency induced by deletion of 1-Ì_å± hydroxylase, mice exhibited smaller lesions similar to those observed in VDR KO mice. Analysis of bone marrow derived macrophages (BMDMs) and bone marrow derived dendritic cells (BMDCs) harvested from VDR KO mice indicates these cells phagocytose L. major parasites at equal levels as WT BMDMs and BMDCs. Examination of parasite clearance mechanisms of BMDMs and BMDCs suggests that VDR plays a role in STAT1 inhibition of iNOS and IL-12p40 up-regulation. Overall, these studies illustrate the importance of vitamin D and VDR in modulation of immune responses to L. major infection.