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

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; Michael Otto; Bas Surewaard; Suranjith L Seneviratne; Dorothy M Grogono; Julien Cachat; Tor Ny; Arthur Kaser; M Estée Török; Sharon J Peacock; Matthew Holden; Tom Blundell; Lihui Wang; Petros Ligoxygakis; Liliana Minichiello; C Geoff Woods; Simon J Foster; Stephen A Renshaw; R Andres Floto

doi:10.1126/science.1258705

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

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, Michael Otto, Bas Surewaard, Suranjith L Seneviratne, Dorothy M Grogono, Julien Cachat, Tor NyArthur Kaser, M Estée Török, Sharon J Peacock, Matthew Holden, Tom Blundell, Lihui Wang, Petros Ligoxygakis, Liliana Minichiello, C Geoff Woods, Simon J Foster, Stephen A Renshaw, R Andres Floto

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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.

Original language	English
Pages (from-to)	641-6
Number of pages	6
Journal	Science
Volume	346
Issue number	6209
DOIs	https://doi.org/10.1126/science.1258705
Publication status	Published - 31 Oct 2014

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Hepburn, L., Prajsnar, T. K., Klapholz, C., Moreno, P., Loynes, C. A., Ogryzko, N. V., Brown, K., Schiebler, M., Hegyi, K., Antrobus, R., Hammond, K. L., Connolly, J., Ochoa, B., Bryant, C., Otto, M., Surewaard, B., Seneviratne, S. L., Grogono, D. M., Cachat, J., ... Floto, R. A. (2014). Innate immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus. Science, 346(6209), 641-6. https://doi.org/10.1126/science.1258705

@article{f9ea92f10a7f478590d999bc4be5099b,

title = "Innate immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus",

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.",

author = "Lucy Hepburn and Prajsnar, \{Tomasz K\} and Catherine Klapholz and Pablo Moreno and Loynes, \{Catherine A\} and Ogryzko, \{Nikolay V\} and Karen Brown and Mark Schiebler and Krisztina Hegyi and Robin Antrobus and Hammond, \{Katherine L\} and John Connolly and Bernardo Ochoa and Clare Bryant and Michael Otto and Bas Surewaard and Seneviratne, \{Suranjith L\} and Grogono, \{Dorothy M\} and Julien Cachat and Tor Ny and Arthur Kaser and T{\"o}r{\"o}k, \{M Est{\'e}e\} and Peacock, \{Sharon J\} and Matthew Holden and Tom Blundell and Lihui Wang and Petros Ligoxygakis and Liliana Minichiello and Woods, \{C Geoff\} and Foster, \{Simon J\} and Renshaw, \{Stephen A\} and Floto, \{R Andres\}",

note = "Copyright {\textcopyright} 2014, American Association for the Advancement of Science. Date of acceptance 02/10/2014",

year = "2014",

month = oct,

day = "31",

doi = "10.1126/science.1258705",

language = "English",

volume = "346",

pages = "641--6",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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Hepburn, L, Prajsnar, TK, Klapholz, C, Moreno, P, Loynes, CA, Ogryzko, NV, Brown, K, Schiebler, M, Hegyi, K, Antrobus, R, Hammond, KL, Connolly, J, Ochoa, B, Bryant, C, Otto, M, Surewaard, B, Seneviratne, SL, Grogono, DM, Cachat, J, Ny, T, Kaser, A, Török, ME, Peacock, SJ, Holden, M, Blundell, T, Wang, L, Ligoxygakis, P, Minichiello, L, Woods, CG, Foster, SJ, Renshaw, SA & Floto, RA 2014, 'Innate immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus', Science, vol. 346, no. 6209, pp. 641-6. https://doi.org/10.1126/science.1258705

TY - JOUR

T1 - Innate immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus

AU - Hepburn, Lucy

AU - Prajsnar, Tomasz K

AU - Klapholz, Catherine

AU - Moreno, Pablo

AU - Loynes, Catherine A

AU - Ogryzko, Nikolay V

AU - Brown, Karen

AU - Schiebler, Mark

AU - Hegyi, Krisztina

AU - Antrobus, Robin

AU - Hammond, Katherine L

AU - Connolly, John

AU - Ochoa, Bernardo

AU - Bryant, Clare

AU - Otto, Michael

AU - Surewaard, Bas

AU - Seneviratne, Suranjith L

AU - Grogono, Dorothy M

AU - Cachat, Julien

AU - Ny, Tor

AU - Kaser, Arthur

AU - Török, M Estée

AU - Peacock, Sharon J

AU - Holden, Matthew

AU - Blundell, Tom

AU - Wang, Lihui

AU - Ligoxygakis, Petros

AU - Minichiello, Liliana

AU - Woods, C Geoff

AU - Foster, Simon J

AU - Renshaw, Stephen A

AU - Floto, R Andres

PY - 2014/10/31

Y1 - 2014/10/31

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84909595112

U2 - 10.1126/science.1258705

DO - 10.1126/science.1258705

M3 - Article

C2 - 25359976

SN - 0036-8075

VL - 346

SP - 641

EP - 646

JO - Science

JF - Science

IS - 6209

ER -

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

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