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

作者：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, Michaël Otto, Bas G. J. Surewaard, Suranjith L. Seneviratne, Dorothy Grogono, Julien Cachat, Tor Ny, Arthur Kaser, M. Estée Török, Sharon J. Peacock, Matthew T. G. Holden, Tom L. Blundell, Lihui Wang, Petros Ligoxygakis, Liliana Minichiello, Caitriona Woods, Simon J. Foster, Stephen A. Renshaw, R. Andrés Floto · 发表于：Science · 年份：2014 · DOI：10.1126/science.1258705 · 被引用次数：81 · 研究领域：Antimicrobial Peptides and Activities、Signaling Pathways in Disease、Nerve injury and regeneration

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.