title: Jagunal homolog 1 is a critical regulator of neutrophil function in fungal host defense.
abstract: Neutrophils are key innate immune effector cells that are essential to fighting bacterial and fungal pathogens. Here we report that mice carrying a hematopoietic lineage-specific deletion of Jagn1 (encoding Jagunal homolog 1) cannot mount an efficient neutrophil-dependent immune response to the human fungal pathogen Candida albicans. Global glycobiome analysis identified marked alterations in the glycosylation of proteins involved in cell adhesion and cytotoxicity in Jagn1-deficient neutrophils. Functional analysis confirmed marked defects in neutrophil migration in response to Candida albicans infection and impaired formation of cytotoxic granules, as well as defective myeloperoxidase release and killing of Candida albicans. Treatment with granulocyte/macrophage colony-stimulating factor (GM-CSF) protected mutant mice from increased weight loss and accelerated mortality after Candida albicans challenge. Notably, GM-CSF also restored the defective fungicidal activity of bone marrow cells from humans with JAGN1 mutations. These data directly identify Jagn1 (JAGN1 in humans) as a new regulator of neutrophil function in microbial pathogenesis and uncover a potential treatment option for humans.
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Wirnsberger
authors.affiliation: Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Zwolanek
authors.affiliation: 1] Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria. [2] Institute for Molecular Pathology (IMP), Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Stadlmann
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Luigi
authors.initials: L
authors.lastname: Tortola
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Shang Wan
authors.initials: SW
authors.lastname: Liu
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Perlot
authors.affiliation: Department of Pediatrics, Dr. Von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.
authors.forename: Päivi
authors.initials: P
authors.lastname: Järvinen
authors.affiliation: 1] Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria. [2] Institute for Molecular Pathology (IMP), Vienna, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dürnberger
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Ivona
authors.initials: I
authors.lastname: Kozieradzki
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Renu
authors.initials: R
authors.lastname: Sarao
authors.affiliation: Campus Science Support Facility (CSF), Vienna, Austria.
authors.forename: Alba
authors.initials: A
authors.lastname: De Martino
authors.affiliation: 1] Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria. [2] Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
authors.affiliation: 1] Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria. [2] Institute for Molecular Pathology (IMP), Vienna, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Mechtler
authors.affiliation: Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Kuchler
authors.affiliation: Department of Pediatrics, Dr. Von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Elling
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D002176:Candida albicans; D002177:Candidiasis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D006031:Glycosylation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology
chemical_list: C000594489:JAGN1 protein, human; D008565:Membrane Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor