Editors' ChoiceImmunology

Overcoming Staph Infections Is Hardwired

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Sci. Signal.  04 Nov 2014:
Vol. 7, Issue 350, pp. ec312
DOI: 10.1126/scisignal.aaa1986

Several evolutionarily conserved components of staphylococcal immunity have been identified using Drosophila as a model organism. However, no vertebrate ortholog has been identified for the Toll ligand Spaetzle, which plays a key role in controlling Gram-positive infection in flies. Hepburn et al. identified NGF-β as a functional equivalent to Spaetzle in vertebrates. Nerve growth factor β (NGF-β) acts as a paracrine “alarmin” orchestrating macrophage and neutrophil responses to Staphylococcus aureus infection. People with deleterious mutations in genes encoding NGF-β or its high-affinity receptor TRKA are predisposed to recurrent and severe staph infections. S. aureus proteins selectively trigger macrophage production of NGF-β, which enhances uptake and superoxide-dependent killing of S. aureus, stimulates proinflammatory cytokine production, and promotes neutrophil recruitment. Moreover, TrkA silencing in vivo increases susceptibility to S. aureus. Thus, the NGF-β–TRKA pathway is a critical, evolutionarily conserved component of vertebrate immunity to S. aureus infection.

L. Hepburn, T. K. Prajsnar, C. Klapholz, P. Moreno, C. A. Loynes, N. V. Ogryzko, K. Brown, M. Schiebler, K. Hegyi, R. Antrobus, K. L. Hammond, J. Connolly, B. Ochoa, C. Bryant, M. Otto, B. Surewaard, S. L. Seneviratne, D. M. Grogono, J. Cachat, T. Ny, A. Kaser, M. E. Török, S. J. Peacock, M. Holden, T. Blundell, L. Wang, P. Ligoxygakis, L. Minichiello, C. G. Woods, S. J. Foster, S. A. Renshaw, R. A. Floto, A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus. Science 346, 641–646 (2014). [Abstract] [Full Text]