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

Abstract

Many key components of innate immunity to infection are shared between Drosophila and humans. However, the fly Toll ligandSpaetzle 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)641-646
Number of pages6
JournalScience
Volume346
Issue number6209
DOIs
Publication statusPublished - 31 Oct 2014

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