Author
Listed:
- Felipe A. Pinho-Ribeiro
(Blavatnik Institute, Harvard Medical School
Washington University School of Medicine in St Louis)
- 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
Harvard Medical School
The Broad Institute of MIT and Harvard)
- 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
Harvard Medical School
The Broad Institute of MIT and Harvard
Boston Children’s Hospital)
- Kelly S. Doran
(University of Colorado Anschutz Medical Campus)
- Dan Levy
(Harvard Medical School
Beth Israel Deaconess Medical Center)
- Isaac M. Chiu
(Blavatnik Institute, Harvard Medical School)
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.
Suggested Citation
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 Steven, 2023.
"Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion,"
Nature, Nature, vol. 615(7952), pages 472-481, March.
Handle:
RePEc:nat:nature:v:615:y:2023:i:7952:d:10.1038_s41586-023-05753-x
DOI: 10.1038/s41586-023-05753-x
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