title: Human Neutrophils Use Different Mechanisms To Kill Aspergillus fumigatus Conidia and Hyphae: Evidence from Phagocyte Defects.
abstract: Neutrophils are known to play a pivotal role in the host defense against Aspergillus infections. This is illustrated by the prevalence of Aspergillus infections in patients with neutropenia or phagocyte functional defects, such as chronic granulomatous disease. However, the mechanisms by which human neutrophils recognize and kill Aspergillus are poorly understood. In this work, we have studied in detail which neutrophil functions, including neutrophil extracellular trap (NET) formation, are involved in the killing of Aspergillus fumigatus conidia and hyphae, using neutrophils from patients with well-defined genetic immunodeficiencies. Recognition of conidia involves integrin CD11b/CD18 (and not dectin-1), which triggers a PI3K-dependent nonoxidative intracellular mechanism of killing. When the conidia escape from early killing and germinate, the extracellular destruction of the Aspergillus hyphae needs opsonization by Abs and involves predominantly recognition via Fcγ receptors, signaling via Syk, PI3K, and protein kinase C to trigger the production of toxic reactive oxygen metabolites by the NADPH oxidase and myeloperoxidase. A. fumigatus induces NET formation; however, NETs did not contribute to A. fumigatus killing. Thus, our findings reveal distinct killing mechanisms of Aspergillus conidia and hyphae by human neutrophils, leading to a comprehensive insight in the innate antifungal response.
authors.affiliation: Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands; r.gazendam@sanquin.nl.
authors.forename: Roel P
authors.initials: RP
authors.lastname: Gazendam
authors.affiliation: Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands;
authors.forename: John L
authors.identifier: http://orcid.org/0000-0002-1113-5707
authors.initials: JL
authors.lastname: van Hamme
authors.affiliation: Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX 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, 1066 CX Amsterdam, the Netherlands;
authors.forename: Mark
authors.initials: M
authors.lastname: Hoogenboezem
authors.affiliation: Department of Pediatric Hematology, Immunology, and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: J Merlijn
authors.initials: JM
authors.lastname: van den Berg
authors.affiliation: Department of Internal Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Jan M
authors.initials: JM
authors.lastname: Prins
authors.affiliation: Department of Zoological Structure Research and Cell Biology, University of Salzburg, 5020 Salzburg, Austria; and.
authors.forename: Ljubomir
authors.identifier: http://orcid.org/0000-0002-1249-0161
authors.initials: L
authors.lastname: Vitkov
authors.affiliation: Nijmegen Center for Infection, Immunity, and Inflammation (N4i), Radboud University, Nijmegen Medical Center, 6525 HP Nijmegen, the Netherlands.
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, 1066 CX 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, 1066 CX 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, 1066 CX Amsterdam, the Netherlands; Department of Pediatric Hematology, Immunology, and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
mesh_terms: D001228:Aspergillosis / Q000276:immunology*; D001232:Aspergillus fumigatus / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D065206:Extracellular Traps / Q000276:immunology; D006801:Humans; D025301:Hyphae / Q000276:immunology*; D007113:Immunity, Innate; D007153:Immunologic Deficiency Syndromes / Q000276:immunology; D018613:Microscopy, Confocal; D009504:Neutrophils / Q000276:immunology*; D010586:Phagocytes / Q000276:immunology; D013172:Spores, Fungal / Q000276:immunology*