Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Bacteria activate sensory neurons that modulate pain and inflammation

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

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

References

  1. Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008)

    ADS  CAS  PubMed  Google Scholar 

  2. White, R. J. Wound infection-associated pain. J. Wound Care 18, 245–249 (2009)

    CAS  PubMed  Google Scholar 

  3. Ren, K. & Dubner, R. Interactions between the immune and nervous systems in pain. Nature Med. 16, 1267–1276 (2010)

    CAS  PubMed  Google Scholar 

  4. Miller, L. S. & Cho, J. S. Immunity against Staphylococcus aureus cutaneous infections. Nature Rev. Immunol. 11, 505–518 (2011)

    CAS  Google Scholar 

  5. Morgan, M. Treatment of MRSA soft tissue infections: an overview. Injury 42 (Suppl. 5). S11–S17 (2011)

    PubMed  Google Scholar 

  6. Bubeck Wardenburg, J., Patel, R. J. & Schneewind, O. Surface proteins and exotoxins are required for the pathogenesis of Staphylococcus aureus pneumonia. Infect. Immun. 75, 1040–1044 (2007)

    PubMed  Google Scholar 

  7. Wang, R. et al. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nature Med. 13, 1510–1514 (2007)

    CAS  PubMed  Google Scholar 

  8. Gordon, R. J. & Lowy, F. D. Pathogenesis of methicillin-resistant Staphylococcus aureus infection. Clin. Infect. Dis. 46 (Suppl. 5). S350–S359 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Diep, B. A. et al. Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus. Lancet 367, 731–739 (2006)

    CAS  PubMed  Google Scholar 

  10. Binshtok, A. M. et al. Nociceptors are interleukin-1β sensors. J. Neurosci. 28, 14062–14073 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang, X. C., Kainz, V., Burstein, R. & Levy, D. Tumor necrosis factor-α induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions. Pain 152, 140–149 (2011)

    CAS  PubMed  Google Scholar 

  12. Müller-Anstett, M. A. et al. Staphylococcal peptidoglycan co-localizes with Nod2 and TLR2 and activates innate immune response via both receptors in primary murine keratinocytes. PLoS ONE 5, e13153 (2010)

    ADS  PubMed  PubMed Central  Google Scholar 

  13. Miller, L. S. et al. MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity 24, 79–91 (2006)

    CAS  PubMed  Google Scholar 

  14. Liu, T. et al. Emerging roles of toll-like receptors in the control of pain and itch. Neurosci. Bull. 28, 131–144 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Diogenes, A. et al. LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J. Dent. Res. 90, 759–764 (2011)

    CAS  PubMed  Google Scholar 

  16. Rigby, K. M. & DeLeo, F. R. Neutrophils in innate host defense against Staphylococcus aureus infections. Semin. Immunopathol. 34, 237–259 (2011)

    PubMed  PubMed Central  Google Scholar 

  17. Rittner, H. L. et al. Mycobacteria attenuate nociceptive responses by formyl peptide receptor triggered opioid peptide release from neutrophils. PLoS Pathog. 5, e1000362 (2009)

    PubMed  PubMed Central  Google Scholar 

  18. Shultz, L. D. et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2Rγ null mice engrafted with mobilized human hemopoietic stem cells. J. Immunol. 174, 6477–6489 (2005)

    CAS  PubMed  Google Scholar 

  19. Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992)

    CAS  PubMed  Google Scholar 

  20. Agarwal, N., Offermanns, S. & Kuner, R. Conditional gene deletion in primary nociceptive neurons of trigeminal ganglia and dorsal root ganglia. Genesis 38, 122–129 (2004)

    CAS  PubMed  Google Scholar 

  21. Le, Y., Murphy, P. M. & Wang, J. M. Formyl-peptide receptors revisited. Trends Immunol. 23, 541–548 (2002)

    CAS  PubMed  Google Scholar 

  22. Liberles, S. D. et al. Formyl peptide receptors are candidate chemosensory receptors in the vomeronasal organ. Proc. Natl Acad. Sci. USA 106, 9842–9847 (2009)

    ADS  CAS  PubMed  Google Scholar 

  23. Rivière, S., Challet, L., Fluegge, D., Spehr, M. & Rodriguez, I. Formyl peptide receptor-like proteins are a novel family of vomeronasal chemosensors. Nature 459, 574–577 (2009)

    ADS  PubMed  Google Scholar 

  24. Southgate, E. L. et al. Identification of formyl peptides from Listeria monocytogenes and Staphylococcus aureus as potent chemoattractants for mouse neutrophils. J. Immunol. 181, 1429–1437 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Lennertz, R. C., Kossyreva, E. A., Smith, A. K. & Stucky, C. L. TRPA1 mediates mechanical sensitization in nociceptors during inflammation. PLoS ONE 7, e43597 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Durr, M. C. et al. Neutrophil chemotaxis by pathogen-associated molecular patterns–formylated peptides are crucial but not the sole neutrophil attractants produced by Staphylococcus aureus. Cell. Microbiol. 8, 207–217 (2006)

    PubMed  Google Scholar 

  27. Inoshima, I. et al. A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nature Med. 17, 1310–1314 (2012)

    Google Scholar 

  28. Kennedy, A. D. et al. Targeting of alpha-hemolysin by active or passive immunization decreases severity of USA300 skin infection in a mouse model. J. Infect. Dis. 202, 1050–1058 (2010)

    PubMed  PubMed Central  Google Scholar 

  29. Dinges, M. M., Orwin, P. M. & Schlievert, P. M. Exotoxins of Staphylococcus aureus. Clin. Microbiol. Rev. 13, 16–34 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wilke, G. A. & Bubeck Wardenburg, J. Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus α-hemolysin-mediated cellular injury. Proc. Natl Acad. Sci. USA 107, 13473–13478 (2010)

    ADS  CAS  PubMed  Google Scholar 

  31. Chiu, I. M., von Hehn, C. A. & Woolf, C. J. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nature Neurosci. 15, 1063–1067 (2012)

    CAS  PubMed  Google Scholar 

  32. Abrahamsen, B. et al. The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 321, 702–705 (2008)

    ADS  CAS  PubMed  Google Scholar 

  33. McLachlan, J. B. et al. Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection. Nature Immunol. 4, 1199–1205 (2003)

    CAS  Google Scholar 

  34. Wong, C. H., Jenne, C. N., Lee, W. Y., Leger, C. & Kubes, P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 334, 101–105 (2011)

    ADS  CAS  Google Scholar 

  35. Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nature Immunol. 13, 1118–1128 (2012)

    CAS  Google Scholar 

  36. Kim, H. K., Thammavongsa, V., Schneewind, O. & Missiakas, D. Recurrent infections and immune evasion strategies of Staphylococcus aureus. Curr. Opin. Microbiol. 15, 92–99 (2011)

    PubMed  PubMed Central  Google Scholar 

  37. Holzmann, B. Modulation of immune responses by the neuropeptide CGRP. Amino Acids 45, 1–7 (2011)

    PubMed  Google Scholar 

  38. Lang, R. & Kofler, B. The galanin peptide family in inflammation. Neuropeptides 45, 1–8 (2010)

    PubMed  Google Scholar 

  39. Pintér, E., Helyes, Z. & Szolcsanyi, J. Inhibitory effect of somatostatin on inflammation and nociception. Pharmacol. Ther. 112, 440–456 (2006)

    PubMed  Google Scholar 

  40. Harzenetter, M. D. et al. Negative regulation of TLR responses by the neuropeptide CGRP is mediated by the transcriptional repressor ICER. J. Immunol. 179, 607–615 (2007)

    CAS  PubMed  Google Scholar 

  41. Gomes, R. N. et al. Calcitonin gene-related peptide inhibits local acute inflammation and protects mice against lethal endotoxemia. Shock 24, 590–594 (2005)

    CAS  PubMed  Google Scholar 

  42. Fernandes, E. S. et al. TRPV1 deletion enhances local inflammation and accelerates the onset of systemic inflammatory response syndrome. J. Immunol. 188, 5741–5751 (2012)

    CAS  PubMed  Google Scholar 

  43. Andersson, U. & Tracey, K. J. Reflex principles of immunological homeostasis. Annu. Rev. Immunol. 30, 313–335 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Sun, J., Singh, V., Kajino-Sakamoto, R. & Aballay, A. Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes. Science 332, 729–732 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rosas-Ballina, M. et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  46. Weihe, E. et al. Molecular anatomy of the neuro-immune connection. Int. J. Neurosci. 59, 1–23 (1991)

    CAS  PubMed  Google Scholar 

  47. Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nature Neurosci. 13, 133–140 (2009)

    PubMed  Google Scholar 

  48. Voehringer, D. et al. Homeostasis and effector function of lymphopenia-induced “memory-like” T cells in constitutively T cell-depleted mice. J. Immunol. 180, 4742–4753 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Pang, Y. Y. et al. agr-Dependent interactions of Staphylococcus aureus USA300 with human polymorphonuclear neutrophils. J. Innate Immun. 2, 546–559 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Schenk, S. & Laddaga, R. A. Improved method for electroporation of Staphylococcus aureus. FEMS Microbiol. Lett. 94, 133–138 (1992)

    CAS  Google Scholar 

  51. Hill, D. R. et al. 2,2,2-Trifluoroethyl fromate: a versatile and selective reagent for the formylation of alcohols, amines, and N-hydroxylamines. Org. Lett. 4, 111–113 (2002)

    ADS  CAS  PubMed  Google Scholar 

  52. Boxio, R. et al. Mouse bone marrow contains large numbers of functionally competent neutrophils. J. Leukoc. Biol. 75, 604–611 (2004)

    CAS  PubMed  Google Scholar 

  53. Sai, J. et al. Parallel phosphatidylinositol 3-kinase (PI3K)-dependent and Src-dependent pathways lead to CXCL8-mediated Rac2 activation and chemotaxis. J. Biol. Chem. 283, 26538–26547 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-33. (PDF 7979 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature12479

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing