tetano
Editor, Senior Moderator
Nature
. 2023 Mar 8.
doi: 10.1038/s41586-023-05796-0. Online ahead of print.
An airway-to-brain sensory pathway mediates influenza-induced sickness
Na-Ryum Bin[SUP] 1 [/SUP], Sara L Prescott[SUP] 1 2 [/SUP], Nao Horio[SUP] 1 [/SUP], Yandan Wang[SUP] 1 [/SUP], Isaac M Chiu[SUP] 3 [/SUP], Stephen D Liberles[SUP] 4 [/SUP]
Affiliations
Abstract
Pathogen infection causes a stereotyped state of sickness that involves neuronally orchestrated behavioural and physiological changes[SUP]1,2[/SUP]. On infection, immune cells release a 'storm' of cytokines and other mediators, many of which are detected by neurons[SUP]3,4[/SUP]; 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) synthesis[SUP]5[/SUP]. A leading model is that PGE2 crosses the blood-brain barrier and directly engages hypothalamic neurons[SUP]2[/SUP]. 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.
. 2023 Mar 8.
doi: 10.1038/s41586-023-05796-0. Online ahead of print.
An airway-to-brain sensory pathway mediates influenza-induced sickness
Na-Ryum Bin[SUP] 1 [/SUP], Sara L Prescott[SUP] 1 2 [/SUP], Nao Horio[SUP] 1 [/SUP], Yandan Wang[SUP] 1 [/SUP], Isaac M Chiu[SUP] 3 [/SUP], Stephen D Liberles[SUP] 4 [/SUP]
Affiliations
- 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 changes[SUP]1,2[/SUP]. On infection, immune cells release a 'storm' of cytokines and other mediators, many of which are detected by neurons[SUP]3,4[/SUP]; 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) synthesis[SUP]5[/SUP]. A leading model is that PGE2 crosses the blood-brain barrier and directly engages hypothalamic neurons[SUP]2[/SUP]. 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.