SummaryLeishmania donovani causes visceral leishmaniasis (VL) where the parasite infects and resides inside liver and spleen tissue macrophages. Given the abnormal lipid profile observed in VL patients, we examined the status of serum lipids in an experimental murine model of VL. The murine VL liver displayed altered expression of lipid metabolic genes, many of which are direct or indirect targets of the liver-specific microRNA-122. Concomitant reduction of miR-122 expression was observed in VL liver. High serum cholesterol caused resistance to L. donovani infection, while downregulation of miR-122 is coupled with low serum cholesterol in VL mice. Exosomes secreted by the infective parasites caused reduction in miR-122 activity in hepatic cells. Leishmania surface glycoprotein gp63, a Zn-metalloprotease, targets pre-miRNA processor Dicer1 to prevent miRNP formation in L. donovani-interacting hepatic cells. Conversely, restoration of miR-122 or Dicer1 levels in VL mouse liver increased serum cholesterol and reduced liver parasite burden.

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The membrane fluidity of antigen-presenting cells (APCs) has a significant bearing on T-cell-stimulating ability and is dependent on the cholesterol content of the membrane. The relationship, if any, between membrane fluidity and defective cell-mediated immunity in visceral leishmaniasis has been investigated. Systemic administration of cholesterol by liposome delivery (cholesterol liposomes) in Leishmania donovaniinfected hamsters was found to cure the infection. Splenic macrophages as a prototype of APCs in infected hamsters had decreased membrane cholesterol and an inability to drive T cells, which was corrected by cholesterol liposome treatment. The effect was cholesterol specific because liposomes made up of the analogue 4-cholesten-3-one provided almost no protection. Infection led to increases in interleukin-10 (IL-10), transforming growth factor beta, and IL-4 signals and concomitant decreases in gamma interferon (IFN-␥), tumor necrosis factor alpha, and inducible NO synthase signals, which reverted upon cholesterol liposome treatment. The antileishmanial T-cell repertoire, whose expansion appeared to be associated with protection, was presumably type Th1, as shown by enhanced IFN-␥ signals and the predominance of the immunoglobulin G2 isotype. The protected group produced significantly more reactive oxygen species and NO than the infected groups, which culminated in killing of L. donovani parasites. Therefore, cholesterol liposome treatment may be yet another simple strategy to enhance the cell-mediated immune response to L. donovani infection. To our knowledge, this is the first report on the therapeutic effect of cholesterol liposomes in any form of the disease.

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