resiniferatoxin and Fasciitis--Necrotizing

The nervous system, the immune system, and microbial pathogens interact closely at barrier tissues. Here, we find that a bacterial pathogen, Streptococcus pyogenes, hijacks pain and neuronal regulation of the immune response to promote bacterial survival. Necrotizing fasciitis is a life-threatening soft tissue infection in which "pain is out of proportion" to early physical manifestations. We find that S. pyogenes, the leading cause of necrotizing fasciitis, secretes streptolysin S (SLS) to directly activate nociceptor neurons and produce pain during infection. Nociceptors, in turn, release the neuropeptide calcitonin gene-related peptide (CGRP) into infected tissues, which inhibits the recruitment of neutrophils and opsonophagocytic killing of S. pyogenes. Botulinum neurotoxin A and CGRP antagonism block neuron-mediated suppression of host defense, thereby preventing and treating S. pyogenes necrotizing infection. We conclude that targeting the peripheral nervous system and blocking neuro-immune communication is a promising strategy to treat highly invasive bacterial infections. VIDEO ABSTRACT.

Topics: Animals; Bacterial Proteins; Botulinum Toxins, Type A; Calcitonin Gene-Related Peptide; Caspase 1; Diterpenes; Fasciitis, Necrotizing; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Neutrophils; Pain; Signal Transduction; Skin; Streptococcal Infections; Streptococcus pyogenes; Streptolysins; TRPV Cation Channels