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.