Lung-innervating nociceptor sensory neurons promote pneumonic sepsis during carbapenem-resistant <i>Klebsiella pneumoniae</i> lung infection

Carbapenem-resistant <i>Klebsiella pneumoniae</i> (CRKP) causes Gram-negative lung infections and fatal pneumonic sepsis for which limited therapeutic options are available. The lungs are densely innervated by nociceptor sensory neurons that mediate breathing, cough, and bronchoconstriction. The role of nociceptors in defense against Gram-negative lung pathogens is unknown. Here, we found that lung-innervating nociceptors promote CRKP pneumonia and pneumonic sepsis. Ablation of nociceptors in mice increased lung CRKP clearance, suppressed trans-alveolar dissemination of CRKP, and protected mice from hypothermia and death. Furthermore, ablation of nociceptors enhanced the recruitment of neutrophils and Ly6C^hi monocytes and cytokine induction. Depletion of Ly6C^hi monocytes, but not of neutrophils, abrogated lung and extrapulmonary CRKP clearance in ablated mice, suggesting that Ly6C^hi monocytes are a critical cellular population to regulate pneumonic sepsis. Further, neuropeptide calcitonin gene-related peptide suppressed the induction of reactive oxygen species in Ly6C^hi monocytes and their CRKP-killing abilities. Targeting nociceptor signaling could be a therapeutic approach for treating multidrug-resistant Gram-negative infection and pneumonic sepsis.