Evidence that Leishmania donovani utilizes a mannose receptor on human mononuclear phagocytes to establish intracellular parasitism.
The pathogenic protozoan Leishmania donovani must gain entrance into mononuclear phagocytes to successfully parasitize man. The parasite's extra-cellular promastigote stage is ingested by human peripheral blood monocytes or monocyte-derived macrophages in the absence of serum, in a manner characteristic of receptor-mediated endocytosis. We have found remarkable similarities between the macrophage receptor(s) for promastigotes and a previously characterized eucaryotic receptor system, the mannose/fucose receptor (MFR), that mediates the binding of zymosan particles and mannose- or fucose-terminal glycoconjugates to macrophages. Ingestion of promastigotes by monocyte-derived macrophages was inhibited by several MFR ligands. Mannan (2.5 mg/ml) decreased ingestion by 63.7% (p less than 0.001), and the neoglycoproteins mannose-BSA and fucose-BSA (20 micrograms/ml) inhibited parasite ingestion by 46.5% and 39.6%, respectively (p less than 0.04). In contrast, promastigote ingestion by monocytes was unaffected by MFR ligands. These results are consistent with reports that MFR activity is present in monocyte-derived macrophages but not in monocytes. Furthermore, attachment of promastigotes to macrophages, assessed by using cytochalasin D to prevent phagocytosis, was reduced 49.8% by mannan. Reorientation of the MFR to the ventral surface of the cell was achieved by plating macrophages onto mannan-coated coverslips, reducing MFR activity on the exposed cell surface by 94% as assessed by binding of 125I-mannose-BSA. Under these conditions, ingestion of promastigotes was inhibited by 71.4% (p less than 0.006). Internalization of the MFR by exposure of macrophages to zymosan before infection with promastigotes resulted in a 62.3% decrease in parasite ingestion (p less than 0.006). Additionally NH4Cl, a weak lysosomotropic base that impairs MFR recycling, decreased macrophage ingestion of promastigotes by 38.2% (p less than 0.03, 30 mM NH4Cl). Subinhibitory concentrations of NH4Cl (10 mM) and of mannan (0.25 mg/ml) together inhibited parasite ingestion by 76.4% (p less than 0.002). These studies suggest that L. donovani promastigotes may utilize a receptor system on human monocyte-derived macrophages, the MFR, to efficiently parasitize the human host.
M E
ME
Wilson
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Pearson
D000328:Adult; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D037181:Lectins, C-Type; D007893:Leishmania donovani / Q000254:growth & development / Q000378:metabolism / Q000469:parasitology*; D008247:Lysosomes / Q000187:drug effects; D008351:Mannans / Q000494:pharmacology; D008358:Mannose / Q000378:metabolism* / Q000494:pharmacology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009000:Monocytes / Q000378:metabolism / Q000469:parasitology*; D010587:Phagocytosis / Q000187:drug effects; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000502:physiology*; D012709:Serum Albumin; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology
D037181:Lectins, C-Type; D008351:Mannans; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D012709:Serum Albumin; C023840:mannose-bovine serum albumin conjugate; D000643:Ammonium Chloride; D012710:Serum Albumin, Bovine; D014357:Trypsin; D008358:Mannose