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

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Science  31 Oct 2014:
Vol. 346, Issue 6209, pp. 641-646
DOI: 10.1126/science.1258705

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Overcoming staph infections is hardwired

Several evolutionarily conserved components of antistaphylococcal immunity have been identified, using Drosophila as a model organism. However, no vertebrate ortholog has been identified for the Toll ligand Spaetzle, which plays a key role in controlling gram-positive infection in flies. Hepburn et al. have now identified NGF-β as a functional equivalent to Spaetzle in vertebrates. NGF-β acts as a paracrine “alarmin” orchestrating macrophage and neutrophil responses to S. aureus infection. People with deleterious mutations in genes encoding NGF-β or its high-affinity receptor TRKA are predisposed to recurrent and severe staph infections. S. aureus proteins selectively trigger macrophage production of NGF-β, which enhances uptake and superoxide-dependent killing of S. aureus, stimulates proinflammatory cytokine production, and promotes neutrophil recruitment. Moreover, TrkA silencing in vivo increases susceptibility to S. aureus. Thus, the NGF-β–TRKA pathway is a critical, evolutionarily conserved component of vertebrate immunity to S. aureus infection.

Science, this issue p. 641

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.

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