Hyperlipidemia offers protection against Leishmania donovani infection: role of membrane cholesterol.
J Lipid Res. 2012 Oct 10. Epub 2012 Oct 10. PMID: 23060454
Indian Institute of Chemical Biology, India;
Leishmania donovani (LD), the causative agent of Visceral Leishmaniasis (VL) extracts membrane cholesterol from macrophage and disrupts lipid rafts leading to their inability to stimulate T cells. Restoration of membrane cholesterol by liposomal delivery corrects above defects and offers protection in infected hamsters. To reinforce further the protective role of cholesterol in VL; mice were either provided high cholesterol (atherogenic) diet or undergone statin treatment. Subsequent LD infection showed that atherogenic diet is associated with protection whereas hypocholesterolemia due to statin treatment confers susceptibility to the infection. This observation was validated in ApoE-/- (AE) mice displaying intrinsic hypercholesterolemia which showed hepatic granuloma, production of host protective cytokines and expansion of antileishmanial CD8(+)IFN-γ(+) and CD8(+)IFN-γ(+)TNF-α(+) T-cells in contrast to the wild type C57BL/6 (BL/6) mice when infected with LD. Normal macrophages from AE mice (N-AE-M) showed three fold higher membrane cholesterol coupled with increased Fluorescence Anisotropy (FA) compared to wild type macrophage (N-BL/6-M). Characterization of in vitro infected AE macrophage (LD-AE-M) revealed intact raft architecture and ability to stimulate T-cell, which were compromised in LD-BL/6-M. This study clearly indicates that hypercholesterolemia, induced intrinsically or extrinsically, can control the pathogenesis of VL by modulating immune repertoire in favour of the host.