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Bacteria activate sensory neurons that modulate pain and inflammation

Nature volume 501, pages 52–57 (2013)Cite this article

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Abstract

Nociceptor sensory neurons are specialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation of pain and eliciting defensive behaviours. Bacterial infections produce pain by unknown molecular mechanisms, although they are presumed to be secondary to immune activation. Here we demonstrate that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils and monocytes is not necessary for Staphylococcus aureus-induced pain in mice. Mechanical and thermal hyperalgesia in mice is correlated with live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxin α-haemolysin, through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host–pathogen interactions.

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Figure 1: Staphylococcus aureus infection induces pain hypersensitivity paralleling bacterial load but not immune activation.
Figure 2: Innate immunity through TLR2 and MyD88 and neutrophils and monocytes is not necessary for pain during S. aureus infection.
Figure 3: Bacterial heat-stable components including N-formylated peptides activate nociceptors.
Figure 4: Heat-sensitive S. aureus αHL activates nociceptors and contributes to infection-induced hyperalgesia.
Figure 5: Nociceptor ablation leads to increased local inflammation and lymphadenopathy after S. aureus infection.
Figure 6: Nociceptor-derived neuropeptides regulate innate immune activation.

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Gene Expression Omnibus

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Microarray data are deposited at the NCBI GEO database under accession number GSE46546.

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Acknowledgements

We thank L. Barrett, V. Wang, N. Andrews, C. Melin, Y. Wang, K. Duong, E. Cobos del Moral, O. Babanyi and G. Bryman for technical help. We thank Y.-C. Cheng and R. Becker for technical advice; J. Sprague and A. Yekkirala for developing whole-well imaging; I. Inoshima for recombinant αHL; R. Malley, J. Steen and Q. Ma for discussions; J. Chiu for moral support; S. Liberles, B. Xu and V. Kuchroo for mentoring. This work was supported by NIH PO1AI078897, 5RO1AI039246 (M.C.C.), R37NS039518, 5P01NS072040 (C.J.W.), 5F32NS076297 (I.M.C.), FACS, and microarrays at Boston Children’s Hospital IDDRC facilities (NIH-P30-HD018655).

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Authors and Affiliations

  1. and Department of Neurobiology, Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Isaac M. Chiu, Nader Ghasemlou, Christian A. Von Hehn, Johnathan Tran, Brian Wainger, Amanda Strominger, Sriya Muralidharan, Sun Wook Hwang & Clifford J. Woolf

  2. Boston Children’s Hospital, Program in Cellular and Molecular Medicine, and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Balthasar A. Heesters & Michael C. Carroll

  3. Medical Microbiology, University Medical Center, Utrecht, Utrecht 3584 CX, The Netherlands,

    Balthasar A. Heesters

  4. Department of Chemistry, Quantitative Biology Program, Brandeis University, Waltham, 02454, Massachusetts, USA

    Fan Zhao

  5. Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, 52242, Iowa, USA

    Alexander R. Horswill

  6. Departments of Pediatrics and of Microbiology, University of Chicago, Chicago, 60637, Illinois, USA

    Juliane Bubeck Wardenburg

  7. Korea University Graduate School of Medicine, Seoul 136-705, South Korea,

    Sun Wook Hwang

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  1. Isaac M. Chiu
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Contributions

I.M.C. and C.J.W. designed the study. I.M.C. and B.A.H.: infection and immune analysis; I.M.C. and N.G.: behavioural analysis; N.G. and A.S.: cytokine profiling; I.M.C. and S.M.: microscopy; I.M.C., C.A.V.H. and J.T.: neuronal culture, calcium imaging; S.W.H.: electrophysiology; F.Z.: peptide synthesis and chemistry; B.W.: multielectrode arrays. J.B.W. and A.R.H.: generation of bacterial strains; J.B.W.: recombinant αHL; J.B.W., M.C.C. and C.J.W.: supervision and expertise. I.M.C. and C.J.W. wrote the manuscript.

Corresponding author

Correspondence to Clifford J. Woolf.

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Chiu, I., Heesters, B., Ghasemlou, N. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52–57 (2013). https://doi.org/10.1038/nature12479

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