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.
Leishmania are intracellular parasites adapted to surviving in macrophages, whose primary function is elimination of invading pathogens. Leishmania entry into host cells is receptor-mediated. These parasites are able to engage multiple host cell-surface receptors, including MR, TLRs, CR3, and FcγRs. Here, we investigated the role of CR3 and FcγR engagement on the maturation of Leishmania-containing phagosomes using CD11b-/- and FcγR-/- macrophages, and assessing EEA1 and lysosome-associated proteins is necessary for the phagosome maturation delay, characteristic of Leishmania infection. Leishmania-containing phagosomes do not fuse with lyosomes until 5 h postinfection in WT mice. Phagolysosome fusion occurs by 1 h in CD11b and FcγR common chain KO macrophages, although receptor deficiency does not influence Leishmania entry or viability. We also investigated the influence of serum components and their effects on phagosome maturation progression. Opsonization with normal mouse serum, complement-deficient serum, or serum from Leishmania-infected mice all influenced phagosome maturation progression. Our results indicate that opsonophagocytosis influences phagosomal trafficking of Leishmania without altering the intracellular fate.
1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and the vitamin D receptor (VDR) are important regulators of autoimmunity. The effect of the VDR on the ability of mice to fight a primary or secondary infection has not been determined. Young and old VDR knockout (KO) mice were able to clear both primary and secondary infections with Listeria monocytogenes. However, the kinetics of clearance was somewhat delayed in the absence of the VDR. Memory T cell development was not different in young VDR KO and wild-type (WT) mice; however, old VDR KO mice had significantly less memory T cells than their WT counterparts but still mounted an adequate immune response as determined by the complete clearance of L. monocytogenes. Although the primary and secondary immune responses were largely intact in the VDR KO mice, the old VDR KO mice had increased cytokines and antibody responses compared with the old WT mice. In particular, old VDR KO mice had elevated antigen non-specific antibodies; however, these magnified immune responses did not correspond to more effective Listeria clearance. The increased antibody and cytokine responses in the old VDR KO mice are consistent with the increased susceptibility of these mice to autoimmunity.
Leishmania major is an obligately intracellular protozoan parasite that causes cutaneous leishmaniasis. Like numerous intracellular pathogens, Leishmania exploits cell surface receptors as a means of entry into host cells. Complement receptor 3 (CR3; also called CD11b/CD18), a  2 integrin on phagocytic cells, is one such receptor. Ligation of CR3 has been shown to inhibit the production of interleukin-12, the cytokine that is pivotal in establishing the cell-mediated response necessary to combat intracellular infection. Here we investigate the role that CR3 plays in the establishment and progression of cutaneous leishmaniaisis in vivo. Dermal lesions of wild-type BALB/c mice are characteristically progressive and lead to extensive tissue necrosis coupled with elevated parasite burdens; CD11b-deficient BALB/c mice, however, demonstrate an intermediate phenotype characterized by chronic lesions and a reduced incidence of tissue damage. Infection followed by a reinfection challenge indicates that both susceptible (BALB/c) and resistant (C57BL/6) mice, regardless of CD11b status, develop resistance to L. major. In addition, CD11b does not bias the T helper cytokine response to L. major infection. Our results further indicate that CD11b is not necessary for disease resolution in resistant mice; rather, this protein appears to play a minor role in susceptibility.Leishmania species are a group of intracellular protozoan parasites that infect cells of the monocyte/macrophage lineage. These parasites cause a range of clinical manifestations, from localized, self-limiting cutaneous lesions to systemic fatal infections. Approximately 350 million people are at risk of infection worldwide (3), and an estimated 2 million new infections occur annually (16).Leishmania entry into host cells is receptor mediated. Leishmania parasites have been shown to engage Fc receptors (FcR) (62), mannose receptor (8), Toll-like receptors 2, 3 (24), and 4 (37), and complement receptor 3 (CR3; also called Mac-1 or ␣ M  2 ) (46); however, the interactions of Leishmania parasites with CR3 have been the best characterized. CR3 is a versatile leukocyte-associated receptor with a number of endogenous and pathogen-associated ligands; as a result, this protein has multiple functions, playing roles in immunity, adhesion, and cell migration (21). Such versatility is a reflection of the structure of CR3 as a heterodimer of CD11b and CD18. Most ligands interact with the CD11b chain lectin and I domains, which recognize mainly pathogen-associated molecules (21) and endogenous ligands (33), respectively. The ligand binding promiscuity of CR3 includes extracellular matrix proteins (63), ICAM-1 (40), and bacterial lipopolysaccharide (LPS) (42). The best-defined function of CR3 is its role as the receptor for C3bi, a complement component protein (35). Interestingly, the predominant Leishmania surface molecule lipophosphoglycan is readily opsonized by complement (17) and binds to CR3 directly (58). Although CR3 is present on the very cells that are meant to c...
SUMMARY Leishmania major is an etiological agent of cutaneous leishmaniasis. The parasite primarily infects immune sentinel cells, specifically macrophages and dendritic cells, in the mammalian host. Infection is receptor mediated and is known to involve parasite binding to cell surface protein complement receptor 3 (CR3, Mac-1, CD11b/CD18). Engagement of CR3 by various ligands inhibits production of interleukin-12 (IL-12), the cytokine that drives anti-leishmanial T helper 1-type immune responses. Likewise, L. major infection inhibits IL-12 production and activation of host macrophages. Our data indicate that in the absence of CR3, L. major-infected bone marrow-derived macrophages produce more IL-12 and nitric oxide compared to WT cells upon LPS stimulation. We therefore investigated multiple signaling pathways by which L. major may inhibit IL-12 transcription through CR3 ligation. We demonstrate that L. major infection does not elicit significant NFκB p65, MAPK, IRF-1, or IRF-8 activation in WT or CD11b deficient macrophages. Furthermore, infection neither inhibits LPS-induced MAPK or NFκB activation, nor blocks IFN-γ-activated IRF-1 and IRF-8. ETS-mediated transcription, however, is inhibited by L. major infection independently of CR3. Our data indicate that L. major mediated inhibition of IL-12 occurs through CR3 engagement, however the mechanism of inhibition is independent of NFκB, MAPK, IRF, and ETS.
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