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Cited by 111Pain Mechanisms and TreatmentsVagus Nerve Stimulation ResearchNeuroscience of respiration and sleep

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

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Bin, Na-Ryum, Prescott, Sara L., Horio, Nao, Wang, Yandan, Chiu, Isaac M., Liberles, Stephen D.·2023·Nature
DOI 10.1038/s41586-023-05796-0PMC PMC10033449
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Abstract

Pathogen infection causes a stereotyped state of sickness that involves neuronally orchestrated behavioural and physiological changes 1,2 . On infection, immune cells release a ‘storm’ of cytokines and other mediators, many of which are detected by neurons 3,4 ; 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) synthesis 5 . A leading model is that PGE2 crosses the blood–brain barrier and directly engages hypothalamic neurons 2 . 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.

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  • Influenza infection may enter the brain through several routes or send deleterious signals to the brain via sensory neurons and trigger neuroinflammation or associated chronic alterations in the CNS.

    “Influenza infection may enter the brain through several routes [122,123] or send deleterious signals to the brain via sensory neurons [124] and trigger neuroinflammation or associated chronic alterations in the CNS [125].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [124]

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Cited by

Sorted by citations

Authors
Bin, N.-R., Prescott, S. L., Horio, N., Wang, Y., Chiu, I. M., & Liberles, S. D.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Harvard University (US)
Corresponding author
Liberles, Stephen D.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-03-08
Volume
615
Issue
7953
Pages
660-667
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-023-05796-0
PMC
PMC10033449
OpenAlex
W4323546561
Cited by
111
References
6
Citations by year
2026: 30 · 2025: 37 · 2024: 28 · 2023: 16
FWCI
19.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL132255)
  • National Center for Complementary and Integrative Health (DP1AT009497)
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
Keywords
sickness behavior, influenza, prostaglandin E2, EP3 receptor, cyclooxygenase-2, neuroimmune interactions, respiratory viral infections, dietary intake, water intake, survival, brainstem projections, axon targeting, nasopharynx, cytokines
MeSH terms
Animals, Behavior, Animal, Blood-Brain Barrier, Brain, Brain Stem, Drinking, Eating, Humans, Influenza, Human, Movement, Nasopharynx, Orthomyxoviridae, Orthomyxoviridae Infections, Receptors, GABA-A, Sensory Receptor Cells, Dinoprostone, Survival Rate, Mice, Cyclooxygenase 2, Receptors, Prostaglandin E, EP3 Subtype

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