title: Innate immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus.
abstract: Many key components of innate immunity to infection are shared between Drosophila and humans. However, the fly Toll ligand Spaetzle is not thought to have a vertebrate equivalent. We have found that the structurally related cystine-knot protein, nerve growth factor β (NGFβ), plays an unexpected Spaetzle-like role in immunity to Staphylococcus aureus infection in chordates. Deleterious mutations of either human NGFβ or its high-affinity receptor tropomyosin-related kinase receptor A (TRKA) were associated with severe S. aureus infections. NGFβ was released by macrophages in response to S. aureus exoproteins through activation of the NOD-like receptors NLRP3 and NLRP4 and enhanced phagocytosis and superoxide-dependent killing, stimulated proinflammatory cytokine production, and promoted calcium-dependent neutrophil recruitment. TrkA knockdown in zebrafish increased susceptibility to S. aureus infection, confirming an evolutionarily conserved role for NGFβ-TRKA signaling in pathogen-specific host immunity.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK.|Department of Medicine, University of Cambridge, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Hepburn
authors.affiliation: Krebs Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.|Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.|Bateson Centre, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
authors.forename: Tomasz K
authors.initials: TK
authors.lastname: Prajsnar
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK.|Department of Medicine, University of Cambridge, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Klapholz
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK.
authors.forename: Pablo
authors.initials: P
authors.lastname: Moreno
authors.affiliation: Bateson Centre, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.|Department of Infection and Immunity, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Loynes
authors.affiliation: Bateson Centre, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Ogryzko
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK.|Department of Medicine, University of Cambridge, UK.|Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Brown
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK.|Department of Medicine, University of Cambridge, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Schiebler
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK.|Department of Medicine, University of Cambridge, UK.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Hegyi
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Antrobus
authors.affiliation: Bateson Centre, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.|Department of Infection and Immunity, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Hammond
authors.affiliation: Krebs Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.|Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
authors.forename: John
authors.initials: J
authors.lastname: Connolly
authors.affiliation: Department of Biochemistry, University of Cambridge, UK.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Ochoa
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Bryant
authors.affiliation: Laboratory of Human Bacterial Pathogenesis NIAID, NIH, Bethesda USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Otto
authors.affiliation: Dept of Medical Microbiology, University Medical Centre, Utrecht, Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Surewaard
authors.affiliation: Department of Clinical Immunology, Royal Free Hospital London, UK.
authors.forename: Suranjith L
authors.initials: SL
authors.lastname: Seneviratne
authors.affiliation: Department of Medicine, University of Cambridge, UK.|Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK.
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: Grogono
authors.affiliation: Dept. of Pathology and Immunology, Geneva University, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Cachat
authors.affiliation: Dept. of Medical Biochemistry and Biophysics, Umea University, Sweden.
authors.forename: Tor
authors.initials: T
authors.lastname: Ny
authors.affiliation: Department of Medicine, University of Cambridge, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Kaser
authors.affiliation: Department of Medicine, University of Cambridge, UK.
authors.forename: M Estée
authors.initials: ME
authors.lastname: Török
authors.affiliation: Department of Medicine, University of Cambridge, UK.|Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Peacock
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Holden
authors.affiliation: Department of Biochemistry, University of Cambridge, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Blundell
authors.affiliation: Biochemistry Department, Oxford University. UK.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Biochemistry Department, Oxford University. UK.
authors.forename: Petros
authors.initials: P
authors.lastname: Ligoxygakis
authors.affiliation: Pharmacology Department, Oxford University. UK.
authors.forename: Liliana
authors.initials: L
authors.lastname: Minichiello
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK.|Department of Medical Genetics, University of Cambridge, UK.
authors.forename: C Geoff
authors.initials: CG
authors.lastname: Woods
authors.affiliation: Krebs Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.|Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Foster
authors.affiliation: Krebs Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.|Bateson Centre, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.|Department of Infection and Immunity, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK.|Department of Medicine, University of Cambridge, UK.|Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK.
authors.forename: R Andres
authors.initials: RA
authors.lastname: Floto
mesh_terms: D000818:Animals; D004331:Drosophila melanogaster / Q000235:genetics / Q000276:immunology; D019143:Evolution, Molecular; D055785:Gene Knockdown Techniques; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000276:immunology; D020932:Nerve Growth Factor / Q000235:genetics / Q000276:immunology*; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D020917:Receptor, trkA / Q000235:genetics / Q000276:immunology*; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology*; D015027:Zebrafish / Q000235:genetics / Q000276:immunology
chemical_list: D020932:Nerve Growth Factor; D020917:Receptor, trkA