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

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.

Evidence for vagal sensory neural involvement in influenza pathogenesis and disease

“…Whether the neuroinflammatory impacts of IAV pathogenesis extend beyond the vagus nerve into the central nervous system and circuits regulated by pulmonary vagal sensory neurons warrants further investigation. Conceivably, central mechanisms could contribute to the myriad of disease behaviours, such as malaise, myalgia, and cough that accompany IAV and other severe lung 378 infections [45,46]. Targeting specific vagal sensory pathways could thus be a potential therapeutic 379 approach to improve IAV disease outcomes.…”

SARS-CoV-2 papain-like protease activates nociceptors to drive sneeze and pain

“…Studies to date have focused on endogenous inflammatory mediators released during viral infection that activate sensory neurons. [12][13][14][15] However, infection also generates viral proteins that may be released and serve as direct host modulatory factors. Viral products are known to activate airway epithelial and immune cells to drive inflammation, but whether viral molecules act directly on sensory neurons to drive pain and airway reflexes is unknown.…”

STEP: profiling cellular-specific targets and pathways of bioactive small molecules in tissues via integrating single-cell transcriptomics and chemoproteomics

“…For instance, aspirin predominantly diminishes the synthesis of PGE2 by inhibiting the activity of PTGS1/2 during anti-inammatory application. 16 However, in the context of anticolorectal cancer, aspirin demonstrates tumor-suppressive properties through multiple pathways, including effecting transcriptional regulation through the acetylation of histones. 14,[17][18][19] Therefore, the target proling of the drug and the specic mechanism of action might be diverse depending on tissue types and disease conditions.…”