| Literature DB >> 25359976 |
Lucy Hepburn1,2, Tomasz K Prajsnar3,4,5, Catherine Klapholz1,2, Pablo Moreno1, Catherine A Loynes5,6, Nikolay V Ogryzko5, Karen Brown1,2,7, Mark Schiebler1,2, Krisztina Hegyi1,2, Robin Antrobus1, Katherine L Hammond5,6, John Connolly3,4, Bernardo Ochoa8, Clare Bryant9, Michael Otto10, Bas Surewaard11, Suranjith L Seneviratne12, Dorothy M Grogono2,7, Julien Cachat13, Tor Ny14, Arthur Kaser2, M Estée Török2, Sharon J Peacock2,15, Matthew Holden15, Tom Blundell8, Lihui Wang16, Petros Ligoxygakis16, Liliana Minichiello17, C Geoff Woods1,18, Simon J Foster3,4, Stephen A Renshaw3,5,6, R Andres Floto1,2,7.
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 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.Entities:
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Year: 2014 PMID： 25359976 PMCID： PMC4255479 DOI： 10.1126/science.1258705
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728