Abstract
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.
Highlights
Visceral leishmaniasis (VL) is caused by the protozoan parasite Leishmania donovani or Leishmania infantum and is the most fatal form of this parasitic disorder (Murray et al, 2005)
The involvement of cholesterol in controlling VL is evident from these studies, little is known about the influence of Leishmania on host lipid metabolism
The miRNA encoding strand of miRNA duplex gets loaded to Argonaute proteins by DICER1 and TAR RNA-binding proteins (TRBPs) to form active microRNA ribonucleoprotein complexes. miR-122, a miRNA expressed abundantly in liver, modulates a wide range of liver functions. miR-122 comprises more than 70% of the liver miRNA pool and is largely responsible for liver homeostasis and lipid metabolism (Chang et al, 2004; Girard et al, 2008)
Summary
Visceral leishmaniasis (VL) is caused by the protozoan parasite Leishmania donovani or Leishmania infantum and is the most fatal form of this parasitic disorder (Murray et al, 2005). The parasite infects the spleen and liver of infected individuals and resides within the macrophages to escape host immune response (Olivier et al, 2005) It shows a dimorphic life cycle, residing as flagellate promastigotes in the midgut of the sand fly vector and as aflagellate amastigotes in the mammalian host (Desjardins and Descoteaux, 1998; Engwerda et al, 2004). In experimental VL, reduced membrane cholesterol in infected macrophages leads to increased membrane fluidity affecting its antigen-presenting ability (Chakraborty et al, 2005). Liposomal formulation of cholesterol is known to offer protection in infected hamsters (Banerjee et al, 2009). L. donovani Exosomes in BALB/c Mice Adult BALB/c mice were injected with NHA-DICER1-expressing plasmids via tail vein. After 2 days, liposomal formulations or leishmanial exosomes were injected through the intracardiac route. Other Experimental Procedures and Details Additional experimental procedures and other essential details on plasmids, oligos, and antibodies used have been provided as Supplemental Experimental Procedures.
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