Innate immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus

Lucy Hepburn; Tomasz K Prajsnar; Catherine Klapholz; Pablo Moreno; Catherine A Loynes; Nikolay V Ogryzko; Karen Brown; Mark Schiebler; Krisztina Hegyi; Robin Antrobus; Katherine L Hammond; John Connolly; Bernardo Ochoa; Clare Bryant; Michael Otto; Bas Surewaard; Suranjith L Seneviratne; Dorothy M Grogono; Julien Cachat; Tor Ny; Arthur Kaser; M Estée Török; Sharon J Peacock; Matthew Holden; Tom Blundell; Lihui Wang; Petros Ligoxygakis; Liliana Minichiello; C Geoff Woods; Simon J Foster; Stephen A Renshaw; R Andres Floto

doi:10.1126/science.1258705

Innate immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus

Science. 2014 Oct 31;346(6209):641-646. doi: 10.1126/science.1258705.

Authors

Lucy Hepburn^#^{1

2}, Tomasz K Prajsnar^#^{3

4

5}, Catherine Klapholz^{1

2}, Pablo Moreno¹, Catherine A Loynes^{5

6}, Nikolay V Ogryzko⁵, Karen Brown^{1

2

7}, Mark Schiebler^{1

2}, Krisztina Hegyi^{1

2}, Robin Antrobus¹, Katherine L Hammond^{5

6}, John Connolly^{3

4}, Bernardo Ochoa⁸, Clare Bryant⁹, Michael Otto¹⁰, Bas Surewaard¹¹, Suranjith L Seneviratne¹², Dorothy M Grogono^{2

7}, Julien Cachat¹³, Tor Ny¹⁴, Arthur Kaser², M Estée Török², Sharon J Peacock^{2

15}, Matthew Holden¹⁵, Tom Blundell⁸, Lihui Wang¹⁶, Petros Ligoxygakis¹⁶, Liliana Minichiello¹⁷, C Geoff Woods^{1

18}, Simon J Foster^{3

4}, Stephen A Renshaw^{3

5

6}, R Andres Floto^{1

2

7}

Affiliations

¹ Cambridge Institute for Medical Research, University of Cambridge, UK.
² Department of Medicine, University of Cambridge, UK.
³ Krebs Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
⁴ Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
⁵ Bateson Centre, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
⁶ Department of Infection and Immunity, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
⁷ Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK.
⁸ Department of Biochemistry, University of Cambridge, UK.
⁹ Department of Veterinary Medicine, University of Cambridge, UK.
¹⁰ Laboratory of Human Bacterial Pathogenesis NIAID, NIH, Bethesda USA.
¹¹ Dept of Medical Microbiology, University Medical Centre, Utrecht, Netherlands.
¹² Department of Clinical Immunology, Royal Free Hospital London, UK.
¹³ Dept. of Pathology and Immunology, Geneva University, Switzerland.
¹⁴ Dept. of Medical Biochemistry and Biophysics, Umea University, Sweden.
¹⁵ Wellcome Trust Sanger Institute, Hinxton, UK.
¹⁶ Biochemistry Department, Oxford University. UK.
¹⁷ Pharmacology Department, Oxford University. UK.
¹⁸ Department of Medical Genetics, University of Cambridge, UK.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Drosophila melanogaster / genetics
Drosophila melanogaster / immunology
Evolution, Molecular
Gene Knockdown Techniques
Host-Pathogen Interactions / genetics
Host-Pathogen Interactions / immunology
Humans
Macrophages / immunology
Nerve Growth Factor / genetics
Nerve Growth Factor / immunology*
Phagocytosis / genetics
Phagocytosis / immunology
Receptor, trkA / genetics
Receptor, trkA / immunology*
Staphylococcal Infections / genetics
Staphylococcal Infections / immunology*
Staphylococcus aureus / immunology*
Zebrafish / genetics
Zebrafish / immunology

Substances

Nerve Growth Factor
Receptor, trkA

Abstract

Publication types

MeSH terms

Substances

Grants and funding