Exploring sensory pathways from the airway to the brain in diseases caused by influenza

In a recent study published in natureResearchers have evaluated the role of sensory pathways from the airway to the brain in diseases caused by influenza.

Study: The sensory pathway from the airway to the brain mediates illness caused by influenza.  Image credit: pinkeyes/Shutterstock.com
Stady: The sensory pathway from the airway to the brain mediates illness caused by influenza. Image credit: pinkeyes/Shutterstock.com


Infection with the pathogen leads to a syndrome characterized by behavioral and physiological changes that are regulated by neurons. During infection, immune cells release a “storm” of cytokines along with other mediators, most of which are sensed by neurons.

However, the neuroimmune interactions and neural circuits that trigger disease behavior during natural infection are not well understood. Aspirin and ibuprofen are commonly used over-the-counter pain relievers that work by inhibiting prostaglandin E2 (PGE2) synthesis.

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In this study, the researchers identified a group of glossopharyngeal sensory neurons that detect PGE2 and are essential for influenza-induced disease in mice.

The team created a mouse model to investigate the neural mechanisms responsible for disease behavior caused by influenza. Mice were infected nasally with influenza A PR/8/34 (H1N1) virus and observed for 10 to 20 days to develop typical disease symptoms.

Many types of neurons, both central and peripheral, express the EP3 receptor. To investigate the primary site of action of the EP3 receptor during influenza-induced illness, mice with an allele for the Cre-dependent deletion of the Ptger3 gene encoding the EP3 receptor were used. The team crossed with a change of 3Phlox mice with Nestin-cre or Advillin-creER mice, directing Cre complex recombination to the majority of central or peripheral neurons and assessing influenza-induced pathological behaviors. At least one week before the virus was inoculated, the team administered tamoxifen to Ptger3Phlox mice to induce Cre-mediated recombination.

The team used gene mapping techniques to identify the neuronal central and peripheral projections of the gamma-aminobutyric acid subunit alpha-1 (GABRA1) receptor. To observe the global nodal-jugular-pituitary projection (NJP) domain, the NJP Ganglia of Gabra1—the internal ribosomal entry site (IRES)—was co-injected with an adenovirus-associated virus (AAV) having a Cre-dependent reporter gene that produces tdTomato or alkaline phosphatase, or AAV that It contains a Cre-independent reporter gene encoding green fluorescent protein (GFP) (AAV-GFP). Then the fibers in the brain and airways were imaged.


Wild mice infected with influenza showed decreased food intake, water consumption, locomotion, body weight, and survival. Six to seven days after infection, the most severe phenotypes emerged in response to viral inoculum concentrations that led to higher pathogenic behavior. Using enzyme-linked immunosorbent assay (ELISA), influenza infection raised PGE2 levels in plasma and bronchoalveolar lavage fluid (BALF) over the same time.

Acute treatment of PGE2 also suppressed food intake, and fibreoptometry studies revealed decreased activity of hypothalamic neurons expressing agouti-related peptide (AGRP), which is associated with a decreased desire to eat rather than a physical inability to eat.

In addition, the team detected a hypothermic response to influenza infection, which is consistent with previous findings in mice. Administration of ibuprofen or aspirin to mice with influenza reduced plasma PGE2 levels, restored eating, water intake, and body weight, and increased infection survival. Mice treated with ibuprofen and aspirin maintained low-level reductions in eating, drinking and locomotion in the absence of elevated PGE2, suggesting that alternative neuroimmune communication pathways may also contribute to the observed behavioral changes. However, ibuprofen and aspirin significantly reduced influenza-induced illness behavior, which was consistent with a major function of cyclooxygenase-2 metabolites within the neuroimmune crosstalk.

Treatment with tamoxifen prior to influenza infection had no effect on the subsequent behavior of control mice. Influenza-induced deficits in feeding, drinking, activity, body weight, and survival were alleviated on Advillin-creER; change 3Phlox Mice equally as administered ibuprofen but remained on Nestin-cre; change 3Phlox the animals. When less lethal amounts of influenza virus were used, deletion of the Ptger3 gene had similar effects on disease onset.

The diverse Cre-identified vagal connections target spatially confined sub-regions of the nucleus of the solitary tract (NTS), with some afferent species also connecting to the postrema area. GABRA1 NJP axons were highly confined to the lateral NTS, not observed in the postrema area, and were distant from NTS regions targeted by other Cre-specific NJP axons, such as enteric neurons identified by expression of Gpr65 or Glyp1R35. These findings further support a model of topographical arrangement in the brainstem, in which neurons that communicate the presence of infection in the airway are spatially separated from some other input.


The results of the study show that deletion of the target EP3 receptors in sensory neurons alters not only pathologic behavior but also the immune response as well as viral transmission from the lower and upper respiratory tract. Knowledge of the multiplicity of sensory pathways of disease and when they are activated by infection with different pathogens will provide a critical framework for decoding this complex and poorly understood physiological state and may facilitate the development of more effective therapies.

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