Published in
American Association for the Advancement of Science, Science, 6209(346), p. 641-646, 2014
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- [eprints.whiterose.ac.uk] | PDF
- [www.researchgate.net] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
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A Spaetzle-like role for nerve growth factor in vertebrate immunity to Staphylococcus aureus
,
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
and other authors.
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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 NLRC4 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.