title: Aspergillus Cell Wall Melanin Blocks LC3-Associated Phagocytosis to Promote Pathogenicity.
abstract: Concealing pathogen-associated molecular patterns (PAMPs) is a principal strategy used by fungi to avoid immune recognition. Surface exposure of PAMPs during germination can leave the pathogen vulnerable. Accordingly, β-glucan surface exposure during Aspergillus fumigatus germination activates an Atg5-dependent autophagy pathway termed LC3-associated phagocytosis (LAP), which promotes fungal killing. We found that LAP activation also requires the genetic, biochemical or biological (germination) removal of A. fumigatus cell wall melanin. The attenuated virulence of melanin-deficient A. fumigatus is restored in Atg5-deficient macrophages and in mice upon conditional inactivation of Atg5 in hematopoietic cells. Mechanistically, Aspergillus melanin inhibits NADPH oxidase-dependent activation of LAP by excluding the p22phox subunit from the phagosome. Thus, two events that occur concomitantly during germination of airborne fungi, surface exposure of PAMPs and melanin removal, are necessary for LAP activation and fungal killing. LAP blockade is a general property of melanin pigments, a finding with broad physiological implications.
authors.affiliation: Department of Medicine, University of Crete, Foundation for Research and Technology, 71300 Heraklion, Crete, Greece.
authors.forename: Tonia
authors.initials: T
authors.lastname: Akoumianaki
authors.affiliation: Department of Medicine, University of Crete, Foundation for Research and Technology, 71300 Heraklion, Crete, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 71300 Heraklion, Crete, Greece.
authors.forename: Irene
authors.initials: I
authors.lastname: Kyrmizi
authors.affiliation: Unité des Aspergillus, Institut Pasteur, Paris 75015, France.
authors.forename: Isabel
authors.initials: I
authors.lastname: Valsecchi
authors.affiliation: Plateforme de Microscopie Electronique, Institut Pasteur, Paris 75015, France; Department of Internal Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Gresnigt
authors.affiliation: Department of Medicine, University of Crete, Foundation for Research and Technology, 71300 Heraklion, Crete, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Samonis
authors.affiliation: Department of Medicine, University of Crete, Foundation for Research and Technology, 71300 Heraklion, Crete, Greece.
authors.forename: Elias
authors.initials: E
authors.lastname: Drakos
authors.affiliation: Department of Medicine, University of Crete, Foundation for Research and Technology, 71300 Heraklion, Crete, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 71300 Heraklion, Crete, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Boumpas
authors.affiliation: Unité des Aspergillus, Institut Pasteur, Paris 75015, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Muszkieta
authors.affiliation: Plateforme de Microscopie Electronique, Institut Pasteur, Paris 75015, France; Department of Internal Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Prevost
authors.affiliation: Department of Infectious Diseases, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
authors.affiliation: Department of Clinical Pathobiochemistry, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: Plateforme de Microscopie Electronique, Institut Pasteur, Paris 75015, France; Department of Internal Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Plateforme de Microscopie Electronique, Institut Pasteur, Paris 75015, France; Department of Internal Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Department of Molecular and Applied Microbiology, Leibniz-Institute for Natural Product Research and Infection Biology (HKI) and Friedrich Schiller University, 07745 Jena, Germany.
authors.forename: Axel A
authors.initials: AA
authors.lastname: Brakhage
authors.affiliation: Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation, 75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence, 75013 Paris, France.
authors.forename: Jamel
authors.initials: J
authors.lastname: El-Benna
authors.affiliation: Unité des Aspergillus, Institut Pasteur, Paris 75015, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Beauvais
authors.affiliation: Unité des Aspergillus, Institut Pasteur, Paris 75015, France. Electronic address: jean-paul.latge@pasteur.fr.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Latge
authors.affiliation: Department of Medicine, University of Crete, Foundation for Research and Technology, 71300 Heraklion, Crete, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 71300 Heraklion, Crete, Greece. Electronic address: hamilos@imbb.forth.gr.
authors.forename: Georgios
authors.initials: G
authors.lastname: Chamilos
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000276:immunology / Q000382:microbiology* / Q000503:physiopathology; D001232:Aspergillus fumigatus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D000071187:Autophagy-Related Protein 5; D002473:Cell Wall / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008543:Melanins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000276:immunology*; D010587:Phagocytosis; D010588:Phagosomes / Q000276:immunology; D014774:Virulence
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; C480860:Map1lc3b protein, mouse; D008543:Melanins; D008869:Microtubule-Associated Proteins