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

Na-Ryum Bin, Sara L. Prescott, Nao Horio, Yandan Wang, Isaac M. Chiu and Stephen D. Liberles ()
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Na-Ryum Bin: Harvard Medical School
Sara L. Prescott: Harvard Medical School
Nao Horio: Harvard Medical School
Yandan Wang: Harvard Medical School
Isaac M. Chiu: Harvard Medical School
Stephen D. Liberles: Harvard Medical School

Nature, 2023, vol. 615, issue 7953, 660-667

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-05796-0

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