title: The β-glucan receptor Dectin-1 activates the integrin Mac-1 in neutrophils via Vav protein signaling to promote Candida albicans clearance.
abstract: Resistance to fungal infections is attributed to engagement of host pattern-recognition receptors, notably the β-glucan receptor Dectin-1 and the integrin Mac-1, which induce phagocytosis and antifungal immunity. However, the mechanisms by which these receptors coordinate fungal clearance are unknown. We show that upon ligand binding, Dectin-1 activates Mac-1 to also recognize fungal components, and this stepwise process is critical for neutrophil cytotoxic responses. Both Mac-1 activation and Dectin-1- and Mac-1-induced neutrophil effector functions require Vav1 and Vav3, exchange factors for RhoGTPases. Mac-1- or Vav1,3-deficient mice have increased susceptibility to systemic candidiasis that is not due to impaired neutrophil recruitment but defective intracellular killing of C. albicans yeast forms, and Mac-1 or Vav1,3 reconstitution in hematopoietic cells restores resistance. Our results demonstrate that antifungal immunity depends on Dectin-1-induced activation of Mac-1 functions that is coordinated by Vav proteins, a pathway that may localize cytotoxic responses of circulating neutrophils to infected tissues.
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.forename: Ahmad
authors.initials: A
authors.lastname: Utomo
authors.forename: Xavier
authors.initials: X
authors.lastname: Cullere
authors.forename: Myunghwan Mark
authors.initials: MM
authors.lastname: Choi
authors.forename: Danny A
authors.initials: DA
authors.lastname: Milner
authors.forename: Deepak
authors.initials: D
authors.lastname: Venkatesh
authors.forename: Seok-Hyun
authors.initials: SH
authors.lastname: Yun
authors.forename: Tanya N
authors.initials: TN
authors.lastname: Mayadas
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000276:immunology* / Q000502:physiology; D002177:Candidiasis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D005260:Female; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology*; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D010587:Phagocytosis; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D000099181:Dectin-1
chemical_list: D037181:Lectins, C-Type; D016177:Macrophage-1 Antigen; D051567:Proto-Oncogene Proteins c-vav; D011971:Receptors, Immunologic; D000099181:Dectin-1; C496619:Vav1 protein, mouse; C496622:Vav3 protein, mouse; C045268:beta-glucan receptor