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 NyArthur 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

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)641-6
Number of pages6
JournalScience
Volume346
Issue number6209
DOIs
Publication statusPublished - 31 Oct 2014

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