| First Author | Pinho-Ribeiro FA | Year | 2023 |
| Journal | Nature | Volume | 615 |
| Issue | 7952 | Pages | 472-481 |
| PubMed ID | 36859544 | Mgi Jnum | J:334146 |
| Mgi Id | MGI:7446860 | Doi | 10.1038/s41586-023-05753-x |
| Citation | Pinho-Ribeiro FA, et al. (2023) Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion. Nature 615(7952):472-481 |
| abstractText | The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache(1,2). Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year(3-5). How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8(+) nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specific RAMP1 deficiency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP-RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis. |
