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Innate immunity. A Spaetzle-like role for nerve growth factor ? 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 ? (NGF?), plays an unexpected Spaetzle-like role in immunity to Staphylococcus aureus infection in chordates. Deleterious mutations of either human NGF? or its high-affinity receptor tropomyosin-related kinase receptor A (TRKA) were associated with severe S. aureus infections. NGF? 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?-TRKA signaling in pathogen-specific host immunity.

SUBMITTER: Hepburn L

PROVIDER: S-EPMC4255479 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Hepburn Lucy L Prajsnar Tomasz K TK Klapholz Catherine C Moreno Pablo P Loynes Catherine A CA Ogryzko Nikolay V NV Ogryzko Nikolay V NV Brown Karen K Schiebler Mark M Hegyi Krisztina K Antrobus Robin R Hammond Katherine L KL Connolly John J Ochoa Bernardo B Bryant Clare C Otto Michael M Surewaard Bas B Seneviratne Suranjith L SL Grogono Dorothy M DM Cachat Julien J Ny Tor T Kaser Arthur A Török M Estée ME Peacock Sharon J SJ Holden Matthew M Blundell Tom T Wang Lihui L Ligoxygakis Petros P Minichiello Liliana L Woods C Geoff CG Foster Simon J SJ Renshaw Stephen A SA Floto R Andres RA

Science (New York, N.Y.) 20141001 6209

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 a ...[more]

PMID: 25359976

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Project description:The human commensal Staphylococcus aureus (SA) is a leading cause of skin/soft tissue and surgical-site infections, and bacteremia. Functional antibodies and T-cell-mediated immunity, particularly Th1/Th17 responses, are thought to mediate protection. Vaccine development may be hindered by modulation of vaccine-induced T cells by pathogen-activated immunoregulatory responses, e.g., via IL-10.We screened SA proteins for CD4+ T-cell-activating and IL-10/IL-17-inducing capacities using healthy donor-derived PBMCs. Responses were characterized (Th1/Th17/Th22/immunosuppressive IL-10-producing cells) using intracellular cytokine staining and flow cytometry. Phenotypic plasticity of Th1/Th17 cells was evaluated under pro- or anti-inflammatory conditions using modulatory cytokines. The impact of vaccination on SA-specific memory responses was assessed using samples from a clinical trial evaluating AS03-adjuvanted and non-adjuvanted multicomponent (CPS5/CPS8/α-toxin/ClfA) vaccines (NCT01160172).The donors exhibited SA-specific memory T-cell responses, indicative of pre-existing immunity to SA. We identified effective activators of Th1 responses (EbhA/IsaA/SdrE/MntC/Aaa/α-toxin), and Th17 and Th1/Th17 responses (EbhA/IsaA/SdrE and, to a lesser extent, α-toxin), but not of Th22 responses or IL-10 production. MRPII, IsdA, and ClfA were inefficient CD4+ T-cell activators in our assays. IL-10, likely produced by innate immune cells, influenced mainly Th1 cells by suppressing IFN-γ production. The memory CD4+ T-cells observed after long-term stimulation with α-toxin and ClfA indicated that vaccination with these proteins had induced expansion of pre-existing Th1 but not Th17 responses, without apparent adjuvant effect, confirming the trial data. The Th1/Th17-driving proteins (EbhA/IsaA/SdrE) shared low IL-10-promoting abilities and restricted phenotypic plasticity under pro- and anti-inflammatory conditions.Given the complex immunopathology and multiple virulence factors, identification of Th1/Th17-driving antigens, adjuvants and administration routes, and delineation of the role of memory responses, may advance vaccine development.

Dataset Information

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

Publications

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

Similar Datasets

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