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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 publication

DOI

10.1126/science.1258705

Type

Journal article

Journal

Science

Publication Date

31/10/2014

Volume

346

Pages

641 - 646

Keywords

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