How the Brain Senses Infection
Summary: A small group of neurons in the airways plays a key role in changing the presence of influenza infection in the brain to the body, and a second pathway from the lungs to the brain becomes active later in the infection. The findings also shed light on how NSAID anti-inflammatory drugs ease flu symptoms.
A new study led by researchers at Harvard Medical School sheds light on how the brain becomes aware that there is an infection in the body.
By studying mice, the team found that a small group of neurons in the airways plays a key role in alerting the brain to a flu infection. They also found signs of a second pathway from the lungs to the brain that becomes active later in the infection.
The study is published in Nature.
Although most people get sick several times a year, scientific knowledge of how the brain evokes feelings of illness has lagged behind research on other bodily states such as hunger and thirst. The paper represents a key first step in understanding the brain-body connection during an infection.
“This study helps us begin to understand a basic mechanism of pathogen detection and how it relates to the nervous system, which until now has been largely mysterious,” said senior author Stephen Liberles, professor of cell biology at the Blavatnik Institute. in HMS and one. investigator at the Howard Hughes Medical Institute.
The findings also shed light on how nonsteroidal anti-inflammatory drugs such as ibuprofen and aspirin ease flu symptoms.
If the results can be translated to humans, the work could have important implications for developing more effective flu therapies.
An infectious state of mind
Liberle’s lab is interested in how the brain and body communicate to control physiology. For example, he has previously explored how the brain processes sensory information from internal organs and how sensory signals can induce or suppress the sensation of nausea.
In the new paper, the researchers turned their attention to another important type of disease that controls the brain: diseases from a respiratory infection.
During an infection, Liberles explained, the brain orchestrates symptoms while the body mounts an immune response. These can include broad symptoms such as fever, decreased appetite and lethargy, as well as specific symptoms such as congestion or cough for a respiratory illness or vomiting or diarrhea for a gastrointestinal bug.
The team decided to focus on influenza, a respiratory virus that is the source of millions of illnesses and medical visits and causes thousands of deaths in the United States each year.
Through a series of experiments in mice, first author Na-Ryum Bin, an HMS researcher in the Liberles lab, identified a small population of neurons embedded in the glossopharyngeal nerve, which runs from the throat to the brain.
Importantly, he found that these neurons are needed to signal to the brain that a flu infection is present and have receptors for lipids called prostaglandins. These lipids are produced by both mice and humans during an infection, and they are targeted by drugs such as ibuprofen and aspirin.
Cutting the glossopharyngeal nerve, eliminating neurons, blocking prostaglandin receptors on those neurons, or treating mice with ibuprofen similarly reduced flu symptoms and increased survival.
Together, the findings suggest that these airway neurons detect prostaglandins created during a flu infection and become a communication channel from the upper throat to the brain.
“We think that these neurons transmit the information that there is a pathogen there and initiate the neural circuits that control the disease response,” Liberles said.
The results provide an explanation for how drugs such as ibuprofen and aspirin work to reduce flu symptoms and suggest that these drugs may even increase survival.
The researchers discovered evidence of another possible pathway for the disease, this one traveling from the lungs to the brain. They found that it appears to become active in the second stage of infection as the virus penetrates deeper into the respiratory system.
The paper represents a key first step in understanding the brain-body connection during an infection. The image is in the public domain
This additional pathway does not involve prostaglandins, the team was surprised to discover. Mice in the second stage of infection did not respond to ibuprofen.
The findings suggest an opportunity to improve flu treatment if scientists are able to develop drugs that target the additional pathway, the authors said.
A basis for future research
The study raises a number of questions that Liberles and colleagues are eager to investigate.
One is how well the findings will translate to humans. Although mice and humans share much basic sensory biology, including having a glossopharyngeal nerve, Liberles stressed that researchers need to conduct further genetic and other experiments to confirm that humans have the same neuronal populations and pathways seen in the study. of the mouse.
If the findings can be replicated in humans, it raises the possibility of developing treatments that address the prostaglandin and non-prostaglandin pathways of influenza infection.
“If you can find a way to disrupt both pathways and use them in synergy, that would be incredibly exciting and potentially transformative,” Liberles said.
Bin is already researching the details of the non-prostaglandin pathway, including the neurons involved, with the goal of understanding how to block it. He also wants to identify the airway cells that produce prostaglandins in the initial pathway and study them in more depth.
Liberles is excited to explore the full variety of disease pathways in the body to learn whether they specialize to different types and sites of infection. Deeper understanding of these pathways, he said, could help scientists learn how to manipulate them to better treat a variety of diseases.
About this neuroscience research news
Author: Press Office
Contact: Press Office – Harvard
Image: Image is in the public domain
Original Research: Open Access.
“A Sensory Pathway from the Airway to the Brain Mediates Influenza-Induced Disease” by Stephen Liberles et al. Nature
A sensory pathway from the airway to the brain mediates influenza-induced illness
Pathogenic infection induces a stereotyped disease state involving orchestrated neuronal physiological and behavioral changes.
With infection, immune cells release a ‘storm’ of cytokines and other mediators, many of which are detected by neurons; however, the neural circuits that respond and the mechanisms of neuro-immune interaction that evoke disease behavior during naturalistic infections remain unclear.
Over-the-counter medications such as aspirin and ibuprofen are widely used to relieve the disease and work by blocking the synthesis of prostaglandin E2 (PGE2). A leading model is that PGE2 crosses the blood-brain barrier and directly engages hypothalamic neurons.
Here, using genetic tools that broadly cover an atlas of peripheral sensory neurons, we instead identified a small population of PGE2-expressing glossopharyngeal sensory neurons (petrosal GABRA1 neurons) that are essential for influenza-induced sickness behavior in mice.
Ablation of petrosal GABRA1 neurons or targeted knockout of the PGE2 receptor 3 (EP3) in these neurons eliminates influenza-induced decreases in food intake, water intake, and motility 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 cyclooxygenase-2 expression after infection, and also display a specific pattern of axonal targeting to the brainstem.
Together, these findings reveal a primary sensory pathway from the airway to the brain that detects locally produced prostaglandins and mediates systemic disease responses to respiratory virus infection.