title: Platelet-activating factor receptor contributes to antileishmanial function of miltefosine.
abstract: Miltefosine [hexadecylphosphocholine (HPC)] is the only orally bioavailable drug for the disease visceral leishmaniasis, which is caused by the protozoan parasite Leishmania donovani. Although miltefosine has direct leishmanicidal effects, evidence is mounting for its immune system-dependent effects. The mechanism of such indirect antileishmanial effects of miltefosine remains to be discovered. As platelet-activating factor and HPC share structural semblances and both induce killing of intracellular Leishmania, we surmised that platelet-activating factor (PAF) receptor had a significant role in the antileishmanial function of miltefosine. The proposition was supported by molecular dynamic simulation of HPC docking into PAF receptor and by comparison of its leishmanicidal function on PAF receptor-deficient macrophages and mice under HPC treatment. We observed that compared with wild-type macrophages, the PAF receptor-deficient macrophages showed 1) reduced binding of a fluorescent analog of HPC, 2) decreased TNF-α production, and 3) lower miltefosine-induced killing of L. donovani. Miltefosine exhibited significantly compromised leishmanicidal function in PAF receptor-deficient mice. An anti-PAF receptor Ab led to a significant decrease in miltefosine-induced intracellular Leishmania killing and IFN-γ production in a macrophage-T cell coculture system. These results indicate significant roles for PAF receptor in the leishmanicidal activity of HPC. The findings open new avenues for a more rational understanding of the mechanism of action of this drug as well as for improved therapeutic strategies.
authors.affiliation: National Centre for Cell Science, Ganeshkhind, Pune 411007, India;
authors.forename: Pallavi R
authors.initials: PR
authors.lastname: Gangalum
authors.affiliation: Nucleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, CEP 35400-000 Ouro Preto, Brazil;
authors.forename: Waldionê
authors.initials: W
authors.lastname: de Castro
authors.affiliation: Nucleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, CEP 35400-000 Ouro Preto, Brazil;
authors.forename: Leda Q
authors.initials: LQ
authors.lastname: Vieira
authors.affiliation: Bose Institute, Kolkata 700 054, India; and.
authors.forename: Ranadhir
authors.initials: R
authors.lastname: Dey
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Unidad Metabolómica, Interacciones y Bioanálisis, Universidad CEU San Pablo, 28040 Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Rivas
authors.affiliation: National Centre for Cell Science, Ganeshkhind, Pune 411007, India;
authors.forename: Shailza
authors.initials: S
authors.lastname: Singh
authors.affiliation: Bose Institute, Kolkata 700 054, India; and.
authors.forename: Subrata
authors.initials: S
authors.lastname: Majumdar
authors.affiliation: National Centre for Cell Science, Ganeshkhind, Pune 411007, India; sahab@nccs.res.in.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Saha
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000953:Antigens, Protozoan / Q000276:immunology; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D055786:Gene Knockout Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D007893:Leishmania donovani / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000953:Antigens, Protozoan; D000981:Antiprotozoal Agents; D008024:Ligands; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D010767:Phosphorylcholine; C039128:miltefosine; D007371:Interferon-gamma