In a recent study published in the journal Cell, Pinho-Ribeiro et al. report that a specific type of bacteria (S. pyogenes), involved in necrotizing fasciitis, increases its infectivity and inhibits tissue immune responses by stimulating local pain neurons. This mechanism suggests that local block of neural activity can be used to increase bacteria clearance and improve tissue survival.
A major manifestation of the necrotizing fasciitis is ‘pain out of proportion’ to physical findings at early time points. The unusual severe and excruciating pain suggests the stimulation of pain neurons.
Necrotizing fasciitis is difficult to treat and has a mortality rate of 24%–32% in developed countries. Thus, amputation is often employed to prevent bacterial metastasis and to decrease mortality.
In the Cell study, the group headed by Isaac Chiu, from the Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA, inoculated mice with S. pyogenesis and observed strong nociceptive behavior (i.e. leg licking/flinching) minutes after the injection. 48h later, the authors observed loss in sensory nerve fibers in the infected area independently on local immune response, indicating that bacteria directly interact with neurons.
The authors report that S. pyogenesis directly stimulates TRPV1+ neurons to produce pain through the action of the secreted pore-forming toxin streptolysin S (SLS). This bacteria produced streptolysin S (SLS) is a pore forming toxin that strongly stimulates pain neurons.
This excessive stimulation of pain neurons elicits their production and release of calcitonin gene-related peptide (CGRP), a neuropeptide that suppresses the recruitment and bactericidal activity of neutrophils essential for host defense.
Of note, when a mutant strain of S. pyogenesis that lacks streptolysin (SLS), a pore forming toxin, or SLS inactivation were employed, less severe nociceptive behavior and improved infection resolution were observed, indicating bacterial SLS in neural modulation. Moreover, local ablation of nociceptor neurons by the administration of the high affinity TRPV-1 agonist, resiniferatoxin (RTX), or botulinum toxin A (BoNT/A) improved neutrophil recruitment and bacterial clearance (despite only RTX decreased nociceptive behavior).
The study identified a critical role for the peripheral nervous system in the regulation of host defense during S. pyogenes invasive infection. The findings in this study strongly indicate that S. pyogenes hijacks pain and neural modulation of immunity to drive bacterial invasion. Importantly, blocking neuro-immunological signaling using BoNT/A or a CGRP antagonist were identified as strategies to treat infections.
Thus, BoNT/A and CGRP antagonists may be repurposed for treatment of infections due to S. pyogenes and perhaps other bacterial pathogens. The authors discuss that targeting the peripheral nervous system could provide therapeutic approaches for invasive infections such as necrotizing fasciitis.