How the brain detects an infection

Summary: A small group of neurons in the airways play a key role in changing the brain from the presence of influenza infection in 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.

Source: Harvard

A new study 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 discovered that a small group of neurons in the airways play a central role in alerting the brain to 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 was published in Nature.

Although most people get sick several times a year, scientific understanding of how the brain evokes feelings of sickness lags behind research on other bodily states such as hunger and thirst. The article represents a key first step in understanding the brain-body connection during 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 lead author Stephen Liberles, Professor of cell biology at the Blavatnik Institute at HMS and a researcher 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 findings can be translated to humans, the work could have important implications for the development of more effective influenza therapies.

A contagious state of mind

Liberles’ 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 evoke or suppress the feeling of nausea.

In the new paper, the researchers turned their attention to another important type of disease that the brain controls: disease due to respiratory infection.

During an infection, Liberles explained, the brain orchestrates the symptoms while the body mounts an immune response. These can include general symptoms such as fever, loss of 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 causes millions of illnesses and medical visits and causes thousands of deaths in the United States each year.

Through a series of mouse experiments, first author Na-Ryum Bin, an HMS researcher in Liberles’ lab, identified a small population of neurons embedded in the glossopharyngeal nerve, which runs from the throat to the brain.

Importantly, he discovered that these neurons are needed to signal to the brain that an influenza infection is present and that they have lipid receptors called prostaglandins. These lipids are made by mice and humans during infection, and they are targeted by drugs such as ibuprofen and aspirin.

Cutting the glossopharyngeal nerve, removing neurons, blocking prostaglandin receptors in these neurons, or treating mice with ibuprofen also reduced flu symptoms and increased survival.

Together, the results suggest that these airway neurons sense prostaglandins produced during influenza infection and become a communication conduit from the upper throat to the brain.

“We think these neurons relay the information that there is a pathogen and initiate neural circuits that control the disease response,” Liberles said.

The results explain how drugs like ibuprofen and aspirin work to reduce flu symptoms and suggest that these drugs may even improve survival.

The researchers found evidence of another potential disease pathway, this one traveling from the lungs to the brain. They found that it appears to become active in the second phase of infection when the virus seeps deeper into the respiratory system.

It shows a brain
The article represents a key first step in understanding the brain-body connection during infection. Image is in public domain

This additional pathway does not involve prostaglandins, the team was surprised to find out. Mice in the second phase of infection did not respond to ibuprofen.

The findings suggest an opportunity to improve influenza 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 his colleagues are eager to explore.

The first is how well the results will translate to humans. Although mice and humans share a lot of basic sensory biology, including the glossopharyngeal nerve, Liberles pointed out that researchers need to conduct further genetic and other experiments to confirm that humans have the same neuron populations and the same pathways than those observed in the mouse study.

If the results can be replicated in humans, it raises the possibility of developing treatments that address both the prostaglandin and non-prostaglandin pathways of influenza infection.

“If you can find a way to inhibit both pathways and use them synergistically, that would be incredibly exciting and potentially transformative,” Liberles said.

See also

This shows a bottle of pills

Bin is already looking into the details of the non-prostaglandin pathway, including the neurons involved, in an effort to figure out how to block it. He also wants to identify airway cells that produce prostaglandins in the initial pathway and study them further.

Liberles is excited to explore the full diversity of disease pathways in the body to find out if they specialize for different types and sites of infection. A better understanding of these pathways, he said, can help scientists learn how to manipulate them to better treat a range of diseases.

About this neuroscience research news

Author: Press office
Source: Harvard
Contact: Press Office – Harvard
Picture: Image is in public domain

Original research: Free access.
“A sensory pathway from the airways to the brain mediates influenza-induced illness” by Stephen Liberles et al. Nature


A sensory pathway from the airways to the brain mediates influenza-induced illness

Pathogen infection causes a stereotypical disease state that involves neuron-orchestrated behavioral and physiological changes.

Upon infection, immune cells release a “storm” of cytokines and other mediators, many of which are sensed by neurons; Yet, the responsive neural circuits and neuroimmune interaction mechanisms 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 prostaglandin E2 (PGE2) synthesis. A key model is that PGE2 crosses the blood-brain barrier and directly engages hypothalamic neurons.

Here, using genetic tools that broadly span an atlas of peripheral sensory neurons, we have instead identified a small population of PGE2-sensing glossopharyngeal sensory neurons (GABRA1 petrosal neurons) that are essential for influenza-induced sickness behavior in the mouse.

Ablation of GABRA1 petrosal neurons or targeted inactivation of the PGE2 3 (EP3) receptor in these neurons eliminates influenza-induced decreases in food intake, water intake, and mobility during infection at an early stage and improves survival. Genetically guided anatomical mapping revealed that GABRA1 petrosal 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 results reveal a primary sensory pathway from the airway to the brain that senses locally produced prostaglandins and mediates systemic disease responses to respiratory virus infection.

Leave a Comment