title: Trehalose dimycolate interferes with FcγR-mediated phagosome maturation through Mincle, SHP-1 and FcγRIIB signalling.
abstract: The causative agent of tuberculosis, Mycobacterium tuberculosis (M. tuberculosis), contains an abundant cell wall glycolipid and a crucial virulence factor, trehalose-6,6'-dimycolate (TDM). TDM causes delay of phagosome maturation and thus promotes survival of mycobacteria inside host macrophages by a not fully understood mechanism. TDM signals through the Monocyte-INducible C-type LEctin (Mincle), a recently identified pattern recognition receptor. Here we show that recruitment of Mincle by TDM coupled to immunoglobulin (Ig)G-opsonised beads during Fcγ receptor (FcγR)-mediated phagocytosis interferes with phagosome maturation. In addition, modulation of phagosome maturation by TDM requires SH2-domain-containing inositol polyphosphate 5' phosphatase (SHP-1) and the FcγRIIB, which strongly suggests inhibitory downstream signalling of Mincle during phagosome formation. Overall, our study reveals important mechanisms contributing to the virulence of TDM.
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, United Kingdom.|Department of Molecular Infection Biology, Research Center Borstel, Borstel, Germany.
authors.forename: Emmanuel C
authors.initials: EC
authors.lastname: Patin
authors.affiliation: Department of Molecular Infection Biology, Research Center Borstel, Borstel, Germany.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Geffken
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Sam
authors.initials: S
authors.lastname: Willcocks
authors.affiliation: Department of Molecular Infection Biology, Research Center Borstel, Borstel, Germany.|German Center for Infection Research, Borstel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Leschczyk
authors.affiliation: Institute for Cell Biology, University of Bonn, Bonn, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Haas
authors.affiliation: Division of Genetics, Department of Biology, University of Erlangen-Nuremberg, Erwin- Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.affiliation: Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Theresa H
authors.initials: TH
authors.lastname: Ward
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, United Kingdom.|Department of Molecular Infection Biology, Research Center Borstel, Borstel, Germany.|German Center for Infection Research, Borstel, Germany.
authors.forename: Ulrich E
authors.initials: UE
authors.lastname: Schaible
mesh_terms: D000818:Animals; D002460:Cell Line; D037181:Lectins, C-Type / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010588:Phagosomes / Q000187:drug effects* / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction; D014199:Trehalose / Q000494:pharmacology*
chemical_list: C113583:Clecsf8 protein, mouse; C499172:Fcgr2b protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D017452:Receptors, IgG; D014199:Trehalose; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse