An airway-to-brain sensory pathway mediates influenza-induced sickness

  • Nature. 2023 Mar;615(7953):660-667. doi: 10.1038/s41586-023-05796-0.
Na-Ryum Bin  1 ,  Sara L Prescott  1  2 ,  Nao Horio  1 ,  Yandan Wang  1 ,  Isaac M Chiu  3 ,  Stephen D Liberles  4
Affiliations
  • 1. Howard Hughes Medical Institute, Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 3. Department of Immunology, Harvard Medical School, Boston, MA, USA.
  • 4. Howard Hughes Medical Institute, Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [email protected].
PMID: 36890237 DOI: 10.1038/s41586-023-05796-0
Abstract

Pathogen Infection causes a stereotyped state of sickness that involves neuronally orchestrated behavioural and physiological changes1,2. On Infection, immune cells release a 'storm' of cytokines and other mediators, many of which are detected by neurons3,4; yet, the responding neural circuits and neuro-immune interaction mechanisms that evoke sickness behaviour during naturalistic infections remain unclear. Over-the-counter medications such as aspirin and ibuprofen are widely used to alleviate sickness and act by blocking prostaglandin E2 (PGE2) synthesis5. A leading model is that PGE2 crosses the blood-brain barrier and directly engages hypothalamic neurons2. Here, using genetic tools that broadly cover a peripheral sensory neuron atlas, we instead identified a small population of PGE2-detecting glossopharyngeal sensory neurons (petrosal GABRA1 neurons) that are essential for influenza-induced sickness behaviour in mice. Ablating petrosal GABRA1 neurons or targeted knockout of PGE2 receptor 3 (EP3) in these neurons eliminates influenza-induced decreases in food intake, water intake and mobility during early-stage Infection and improves survival. Genetically guided anatomical mapping revealed that petrosal GABRA1 neurons project to mucosal regions of the nasopharynx with increased expression of cyclooxygenase-2 after Infection, and also display a specific axonal targeting pattern in the brainstem. Together, these findings reveal a primary airway-to-brain sensory pathway that detects locally produced Prostaglandins and mediates systemic sickness responses to respiratory virus Infection.