title: Dectin-1 Controls TLR9 Trafficking to Phagosomes Containing β-1,3 Glucan.
abstract: Dectin-1 and TLR9 play distinct roles in the recognition and induction of innate immune responses to Aspergillus fumigatus and Candida albicans. Dectin-1 is a receptor for the major fungal cell wall carbohydrate β-1,3 glucan that induces inflammatory cytokines and controls phagosomal maturation through spleen tyrosine kinase activation. TLR9 is an endosomal TLR that also modulates the inflammatory cytokine response to fungal pathogens. In this study, we demonstrate that β-1,3 glucan beads are sufficient to induce dynamic redistribution and accumulation of cleaved TLR9 to phagosomes. Trafficking of TLR9 to A. fumigatus and C. albicans phagosomes requires Dectin-1 recognition. Inhibition of phagosomal acidification blocks TLR9 accumulation on phagosomes containing β-1,3 glucan beads. Dectin-1-mediated spleen tyrosine kinase activation is required for TLR9 trafficking to β-1,3 glucan-, A. fumigatus-, and C. albicans-containing phagosomes. In addition, Dectin-1 regulates TLR9-dependent gene expression. Collectively, our study demonstrates that recognition of β-1,3 glucan by Dectin-1 triggers TLR9 trafficking to β-1,3 glucan-containing phagosomes, which may be critical in coordinating innate antifungal defense.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114; Biomedical Engineering and Biotechnology, University of Massachusetts, Lowell, MA 01854;
authors.forename: Nida S
authors.identifier: http://orcid.org/0000-0002-5448-8289
authors.initials: NS
authors.lastname: Khan
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA 02142;
authors.forename: Pia V
authors.identifier: http://orcid.org/0000-0002-6364-9435
authors.initials: PV
authors.lastname: Kasperkovitz
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Allison K
authors.identifier: http://orcid.org/0000-0002-8412-315X
authors.initials: AK
authors.lastname: Timmons
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114; Department of Medicine, Harvard Medical School, Boston, MA 02115;
authors.forename: Michael K
authors.initials: MK
authors.lastname: Mansour
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Tam
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Michael W
authors.identifier: http://orcid.org/0000-0002-4813-6308
authors.initials: MW
authors.lastname: Seward
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114; Department of Medicine, Harvard Medical School, Boston, MA 02115;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Reedy
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Sravanthi
authors.initials: S
authors.lastname: Puranam
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114; Nutrition and Metabolism, Boston University, Boston, MA 02118; and.
authors.forename: Marianela
authors.initials: M
authors.lastname: Feliu
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114; Department of Medicine, Harvard Medical School, Boston, MA 02115; Program in Immunology, Harvard Medical School, Boston, MA 02115 jvyas@partners.org.
authors.forename: Jatin M
authors.identifier: http://orcid.org/0000-0002-9985-9565
authors.initials: JM
authors.lastname: Vyas
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology; D002176:Candida albicans / Q000276:immunology; D002460:Cell Line; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D006863:Hydrogen-Ion Concentration; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008954:Models, Biological; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism*; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D047071:beta-Glucans / Q000378:metabolism*; D000099181:Dectin-1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D051217:Toll-Like Receptor 9; D047071:beta-Glucans; D000099181:Dectin-1; C000606896:SYK protein, human; C000606897:Syk protein, mouse
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