Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion

Felipe A. Pinho-Ribeiro, Liwen Deng, Dylan V. Neel, Ozge Erdogan, Himanish Basu, Daping Yang, Samantha Choi, Alec J. Walker, Simone Carneiro-Nascimento, Kathleen He, Glendon Wu, Beth Stevens, Kelly S. Doran, Dan Levy and Isaac M. Chiu ()
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Felipe A. Pinho-Ribeiro: Blavatnik Institute, Harvard Medical School
Liwen Deng: Blavatnik Institute, Harvard Medical School
Dylan V. Neel: Blavatnik Institute, Harvard Medical School
Ozge Erdogan: Harvard School of Dental Medicine
Himanish Basu: Blavatnik Institute, Harvard Medical School
Daping Yang: Blavatnik Institute, Harvard Medical School
Samantha Choi: Blavatnik Institute, Harvard Medical School
Alec J. Walker: Boston Children’s Hospital
Simone Carneiro-Nascimento: Beth Israel Deaconess Medical Center
Kathleen He: Blavatnik Institute, Harvard Medical School
Glendon Wu: Blavatnik Institute, Harvard Medical School
Beth Stevens: Boston Children’s Hospital
Kelly S. Doran: University of Colorado Anschutz Medical Campus
Dan Levy: Harvard Medical School
Isaac M. Chiu: Blavatnik Institute, Harvard Medical School

Nature, 2023, vol. 615, issue 7952, 472-481

Abstract: Abstract The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year3–5. 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.

Date: 2023
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DOI: 10.1038/s41586-023-05753-x

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