title: Bruton's Tyrosine Kinase (BTK) and Vav1 contribute to Dectin1-dependent phagocytosis of Candida albicans in macrophages.
abstract: Phagocytosis of the opportunistic fungal pathogen Candida albicans by cells of the innate immune system is vital to prevent infection. Dectin-1 is the major phagocytic receptor involved in anti-fungal immunity. We identify two new interacting proteins of Dectin-1 in macrophages, Bruton's Tyrosine Kinase (BTK) and Vav1. BTK and Vav1 are recruited to phagocytic cups containing C. albicans yeasts or hyphae but are absent from mature phagosomes. BTK and Vav1 localize to cuff regions surrounding the hyphae, while Dectin-1 lines the full length of the phagosome. BTK and Vav1 colocalize with the lipid PI(3,4,5)P3 and F-actin at the phagocytic cup, but not with diacylglycerol (DAG) which marks more mature phagosomal membranes. Using a selective BTK inhibitor, we show that BTK contributes to DAG synthesis at the phagocytic cup and the subsequent recruitment of PKCε. BTK- or Vav1-deficient peritoneal macrophages display a defect in both zymosan and C. albicans phagocytosis. Bone marrow-derived macrophages that lack BTK or Vav1 show reduced uptake of C. albicans, comparable to Dectin1-deficient cells. BTK- or Vav1-deficient mice are more susceptible to systemic C. albicans infection than wild type mice. This work identifies an important role for BTK and Vav1 in immune responses against C. albicans.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Karin
authors.initials: K
authors.lastname: Strijbis
authors.forename: Fikadu G
authors.initials: FG
authors.lastname: Tafesse
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Fairn
authors.forename: Martin D
authors.initials: MD
authors.lastname: Witte
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Dougan
authors.forename: Nicki
authors.initials: N
authors.lastname: Watson
authors.forename: Eric
authors.initials: E
authors.lastname: Spooner
authors.forename: Alexandre
authors.initials: A
authors.lastname: Esteban
authors.forename: Valmik K
authors.initials: VK
authors.lastname: Vyas
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Fink
authors.forename: Sergio
authors.initials: S
authors.lastname: Grinstein
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
mesh_terms: D000199:Actins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002176:Candida albicans / Q000276:immunology* / Q000378:metabolism; D002177:Candidiasis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004075:Diglycerides / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology*; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D000199:Actins; D000077329:Agammaglobulinaemia Tyrosine Kinase; D004075:Diglycerides; D018398:Homeodomain Proteins; D037181:Lectins, C-Type; D009479:Neuropeptides; D018129:Phosphatidylinositol Phosphates; D011505:Protein-Tyrosine Kinases; D000099181:Dectin-1; C485177:Vax1 protein, mouse; C060974:phosphatidylinositol 3,4,5-triphosphate; C000625951:Btk protein, mouse