RESUMO
Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response. Here, we show that Nav1.8+ sensory neurons, which are involved in pain perception, control the magnitude of CD8 T cell priming and expansion in HSV-1-infected mice. The ablation of Nav1.8-expressing sensory neurons is associated with extensive skin lesions characterized by enhanced inflammatory cytokine and chemokine production. Mechanistically, Nav1.8+ sensory neurons are required for the downregulation of neutrophil infiltration in the skin after viral clearance to limit the severity of tissue damage and restore skin homeostasis, as well as for eliciting robust CD8 T cell priming in skin-draining lymph nodes by controlling dendritic cell responses. Collectively, our data reveal an important role for the sensory nervous system in regulating both innate and adaptive immune responses to viral infection, thereby opening up possibilities for new therapeutic strategies.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Dor Nociceptiva/imunologia , Células Receptoras Sensoriais/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Herpes Simples/genética , Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Canal de Sódio Disparado por Voltagem NAV1.8/imunologia , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Infiltração de Neutrófilos/imunologia , Dor Nociceptiva/genética , Dor Nociceptiva/metabolismo , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/virologia , Pele/imunologia , Pele/metabolismo , Pele/virologiaRESUMO
Nociceptor sensory neurons are specialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation of pain and eliciting defensive behaviours. Bacterial infections produce pain by unknown molecular mechanisms, although they are presumed to be secondary to immune activation. Here we demonstrate that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils and monocytes is not necessary for Staphylococcus aureus-induced pain in mice. Mechanical and thermal hyperalgesia in mice is correlated with live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxin α-haemolysin, through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host-pathogen interactions.