Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314

Kimbria J. Blake, Pankaj Baral, Tiphaine Voisin, Ashira Lubkin, Felipe Almeida Pinho-Ribeiro, Kelsey L. Adams, David P. Roberson, Yuxin C. Ma, Michael Otto, Clifford J. Woolf, Victor J. Torres and Isaac M. Chiu ()
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Kimbria J. Blake: Division of Immunology, Harvard Medical School
Pankaj Baral: Division of Immunology, Harvard Medical School
Tiphaine Voisin: Division of Immunology, Harvard Medical School
Ashira Lubkin: New York University School of Medicine
Felipe Almeida Pinho-Ribeiro: Division of Immunology, Harvard Medical School
Kelsey L. Adams: Division of Immunology, Harvard Medical School
David P. Roberson: Harvard Medical School
Yuxin C. Ma: Division of Immunology, Harvard Medical School
Michael Otto: Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Disease, National Institutes of Health
Clifford J. Woolf: Harvard Medical School
Victor J. Torres: New York University School of Medicine
Isaac M. Chiu: Division of Immunology, Harvard Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract The hallmark of many bacterial infections is pain. The underlying mechanisms of pain during live pathogen invasion are not well understood. Here, we elucidate key molecular mechanisms of pain produced during live methicillin-resistant Staphylococcus aureus (MRSA) infection. We show that spontaneous pain is dependent on the virulence determinant agr and bacterial pore-forming toxins (PFTs). The cation channel, TRPV1, mediated heat hyperalgesia as a distinct pain modality. Three classes of PFTs—alpha-hemolysin (Hla), phenol-soluble modulins (PSMs), and the leukocidin HlgAB—directly induced neuronal firing and produced spontaneous pain. From these mechanisms, we hypothesized that pores formed in neurons would allow entry of the membrane-impermeable sodium channel blocker QX-314 into nociceptors to silence pain during infection. QX-314 induced immediate and long-lasting blockade of pain caused by MRSA infection, significantly more than lidocaine or ibuprofen, two widely used clinical analgesic treatments.

Date: 2018
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DOI: 10.1038/s41467-017-02448-6

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