title: Two independent killing mechanisms of Candida albicans by human neutrophils: evidence from innate immunity defects.
abstract: Invasive fungal infections, accompanied by high rates of mortality, represent an increasing problem in medicine. Neutrophils are the major effector immune cells in fungal killing. Based on studies with neutrophils from patients with defined genetic defects, we provide evidence that human neutrophils use 2 distinct and independent phagolysosomal mechanisms to kill Candida albicans. The first mechanism for the killing of unopsonized C albicans was found to be dependent on complement receptor 3 (CR3) and the signaling proteins phosphatidylinositol-3-kinase and caspase recruitment domain-containing protein 9 (CARD9), but was independent of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The second mechanism for the killing of opsonized C albicans was strictly dependent on Fcγ receptors, protein kinase C (PKC), and reactive oxygen species production by the NADPH oxidase system. Each of the 2 pathways of Candida killing required Syk tyrosine kinase activity, but dectin-1 was dispensable for both of them. These data provide an explanation for the variable clinical presentation of fungal infection in patients suffering from different immune defects, including dectin-1 deficiency, CARD9 deficiency, or chronic granulomatous disease.
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Roel P
authors.initials: RP
authors.lastname: Gazendam
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: John L
authors.initials: JL
authors.lastname: van Hamme
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Anton T J
authors.initials: AT
authors.lastname: Tool
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Michel
authors.initials: M
authors.lastname: van Houdt
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Paul J J H
authors.initials: PJ
authors.lastname: Verkuijlen
authors.affiliation: University Children's Hospital, Paediatric Infectious Diseases and Immunology, University of Würzburg, Würzburg, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Herbst
authors.affiliation: University Children's Hospital, Paediatric Infectious Diseases and Immunology, University of Würzburg, Würzburg, Germany;
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Liese
authors.affiliation: Nijmegen Center for Infection, Immunity and Inflammation (N4i), Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands; and.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Dirk
authors.initials: D
authors.lastname: Roos
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Timo K
authors.initials: TK
authors.lastname: van den Berg
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
mesh_terms: D002176:Candida albicans / Q000254:growth & development / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D002478:Cells, Cultured; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072377:Syk Kinase; D000099181:Dectin-1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D019255:NADPH Oxidases; D011493:Protein Kinase C; D011505:Protein-Tyrosine Kinases; D017382:Reactive Oxygen Species; D017452:Receptors, IgG; D000072377:Syk Kinase; D000099181:Dectin-1; C489017:FCGR1A protein, human; C000606896:SYK protein, human