Respiratory infections caused by influenza and other pathogens can lead to sickness characterized by coordinated behavioral and physiological changes. These responses, which include fever, lethargy, loss of appetite, and decreased mobility, are thought to be initiated by neuro-immune interactions. However, the specific neural circuits and pathways involved in these responses still need to be fully understood.
A recent study has identified a previously unknown airway-to-brain sensory pathway that plays a critical role in influenza-induced sickness. This pathway involves a small population of glossopharyngeal sensory neurons that detect locally produced prostaglandins and mediate systemic sickness responses to respiratory virus infection. Understanding the mechanisms behind this pathway could lead to new treatments for respiratory infections and associated sickness behaviors.
A new study published in Nature has shed light on the neural mechanisms underlying sickness behavior caused by pathogen infections. The study, conducted on mice, identified a small population of PGE2-detecting glossopharyngeal sensory neurons essential for influenza-induced sickness behavior. The researchers employed genetic tools to map sensory neurons in the periphery in great detail.
They found that ablation of petrosal GABRA1 neurons or targeted deletion of PGE2 receptor 3 (EP3) in these neurons improves survival by lowering influenza-induced impairments in food intake, water intake, and mobility in the early stages of illness. Petrosal GABRA1 neurons have been found to have a specific axonal targeting pattern in the brainstem and to project to mucosal areas of the nasopharynx with increased expression of cyclooxygenase-2 following infection using genetically driven anatomical mapping.
Our findings reveal a significant sensory route from the airways to the brain that may detect locally generated prostaglandins and improve systemic disease responses to respiratory virus infection. The contemporary COVID-19 pandemic has had far-reaching consequences on human civilization, as respiratory illnesses produced by influenza and other microorganisms are the significant causes of mortality and hospitalization globally. Sickness may be highly incapacitating, and most people experience it many times per year.
A history of illness suggests that the brain’s response to infection may give a highly coordinated and adaptable method to help recovery. Animals infected with various pathogens display common behavioral and physiological responses, including fever, lethargy, loss of appetite, headache, pain, mood changes, and decreased socialization. This suggests a common sickness state involving shared neural circuits. In addition to common symptoms, other sickness responses are tailored to the site of infection, suggesting multiple body–brain communication pathways for pathogen detection.
Researchers have found that a small cluster of glossopharyngeal sensory neurons plays a significant role in detecting PGE2, a prostaglandin produced during respiratory viral infections such as influenza. The sensory neurons induce a neuronally orchestrated state of sickness, and various behavioral responses are associated with respiratory viral infections.
Glossopharyngeal nerve transection, ibuprofen, aspirin, EP3 receptor antagonism, targeted EP3 receptor knockout, and targeted neuronal ablation all showed that sickness behaviors were attenuated but not eliminated. Additionally, the study suggests that there are likely to be two phases of influenza-induced sickness behavior, with a second phase independent of PGE2, EP3, and glossopharyngeal sensory neurons.
Overall, the study provides new insights into the neural mechanisms underlying sickness behavior caused by pathogen infections and could help develop new treatments for respiratory infections caused by influenza and other pathogens.
