Editors' ChoiceHost-Pathogen Interactions

A painful takedown of host defenses

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Science Signaling  12 Jun 2018:
Vol. 11, Issue 534, eaau4230
DOI: 10.1126/scisignal.aau4230

A flesh-eating bacterium disables host defenses by inducing pain-sensing neurons to release a neutrophil-inhibiting peptide.

The high mortality rate of necrotizing fasciitis is caused by the aggressive, difficult-to-control destruction of subcutaneous tissue and underlying fascia by Gram-positive bacteria, such as Streptococcus pyogenes. The excruciating pain experienced by patients is disproportionate to the tissue damage and correlates with the severity of the disease. Pinho-Ribeiro et al. (see commentary by Tracey) investigated the relationship between the pain induced by S. pyogenes and the pathogenesis of necrotizing fasciitis. Mice infected with S. pyogenes strains isolated from human infections showed inflammation-independent pain responses and mechanical and heat hyperalgesia at the infection site. S. pyogenes activated Ca2+ signaling in nociceptor neurons that were positive for the cation channel TRPV1. This activation required the pore-forming toxin streptolysin S (SLS) and resulted in release of the neuropeptide CGRP (calcitonin gene-related peptide). Application of CGRP prevented neutrophils from killing S. pyogenes. In addition, SLS was required for the pain and mechanical hyperalgesia induced by S. pyogenes infection. Genetic or pharmacological ablation of TRPV1-positive neurons reduced disease progression and increased recovery in mice, effects that were mimicked by subcutaneous injection of botulinum neurotoxin A (to prevent neuropeptide release) or a CGRP receptor antagonist. These results suggest that preventing the activation of nociceptor neurons may be a therapeutic strategy to limit the progression of necrotizing fasciitis and the need for drastic measures such as limb amputation.

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