Journal
SCIENCE
Volume 346, Issue 6209, Pages 641-646Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1258705
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Funding
- Wellcome Trust [084953, 089981]
- Wellcome Trust [Medical Research Council, UK] [G0700091, G0701932]
- Papworth Hospital
- National Institute for Health Research Cambridge Biomedical Research Centre
- NIAID, NIH
- Academy of Medical Sciences (AMS) [AMS-CSF4-Torok] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/K006436/1] Funding Source: researchfish
- Medical Research Council [MR/M004864/1, G0701932, MR/K006312/1, G0700091B, G0300170, G108/595, G0700091] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [NC/K500392/1] Funding Source: researchfish
- BBSRC [BB/K006436/1] Funding Source: UKRI
- MRC [MR/M004864/1, G0701932, G0300170, G108/595, MR/K006312/1] Funding Source: UKRI
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Many key components of innate immunity to infection are shared between Drosophila and humans. However, the fly Toll ligandSpaetzle is not thought to have a vertebrate equivalent. We have found that the structurally related cystine-knot protein, nerve growth factor beta (NGF beta), plays an unexpected Spaetzle-like role in immunity to Staphylococcus aureus infection in chordates. Deleterious mutations of either human NGF beta or its high-affinity receptor tropomyosin-related kinase receptor A (TRKA) were associated with severe S. aureus infections. NGF beta 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 NGF beta-TRKA signaling in pathogen-specific host immunity.
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