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 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

Research output: Contribution to journal › Article › peer-review

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

Access to Document

10.1126/science.1258705

Handle.net

Persistent link to portal record

Cite this

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",

number = "6209",

}

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.

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

Abstract

Access to Document

Handle.net

Fingerprint

Cite this