title: The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis.
abstract: Mycobacterium tuberculosis (M.tb) survives in macrophages in part by limiting phagosome-lysosome (P-L) fusion. M.tb mannose-capped lipoarabinomannan (ManLAM) blocks phagosome maturation. The pattern recognition mannose receptor (MR) binds to the ManLAM mannose caps and mediates phagocytosis of bacilli by human macrophages. Using quantitative electron and confocal microscopy, we report that engagement of the MR by ManLAM during the phagocytic process is a key step in limiting P-L fusion. P-L fusion of ManLAM microspheres was significantly reduced in human macrophages and an MR-expressing cell line but not in monocytes that lack the receptor. Moreover, reversal of P-L fusion inhibition occurred with MR blockade. Inhibition of P-L fusion did not occur with entry via Fcgamma receptors or dendritic cell-specific intracellular adhesion molecule 3 grabbing nonintegrin, or with phosphatidylinositol-capped lipoarabinomannan. The ManLAM mannose cap structures were necessary in limiting P-L fusion, and the intact molecule was required to maintain this phenotype. Finally, MR blockade during phagocytosis of virulent M.tb led to a reversal of P-L fusion inhibition in human macrophages (84.0 +/- 5.1% vs. 38.6 +/- 0.6%). Thus, engagement of the MR by ManLAM during the phagocytic process directs M.tb to its initial phagosomal niche, thereby enhancing survival in human macrophages.
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Kang
authors.forename: Abul K
authors.initials: AK
authors.lastname: Azad
authors.forename: Jordi B
authors.initials: JB
authors.lastname: Torrelles
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kaufman
authors.forename: Alison
authors.initials: A
authors.lastname: Beharka
authors.forename: Eric
authors.initials: E
authors.lastname: Tibesar
authors.forename: Lucy E
authors.initials: LE
authors.lastname: DesJardin
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
mesh_terms: D000818:Animals; D019556:COS Cells; D002459:Cell Fusion; D002522:Chlorocebus aethiops; D017931:DNA Primers; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D009169:Mycobacterium tuberculosis / Q000378:metabolism* / Q000648:ultrastructure; D010587:Phagocytosis / Q000502:physiology*; D010588:Phagosomes / Q000378:metabolism* / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; C050016:lipoarabinomannan