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Why does the flu make you feel so crummy? Neurons in throat may be to blame

When you come down with the flu, your body lets you know. You lose your appetite, you feel sluggish, and your mood takes a hit. The infection itself doesn’t cause these symptoms—your brain does.

Now, scientists may have figured out a key part of how this happens. Studying mice with influenza, they found a cluster of nerve cells in the back of the throat that detects a virus’ presence and sends signals to the brain, triggering symptoms that respond to the infection.

The study is among the first to pin this response on a specific population of nerve cells, says Anoj Ilanges, a biologist at the Howard Hughes Medical Institute’s Janelia Research Campus who was not involved in the work. “They’ve done a really great job of looking at this comprehensively.”

Scientists know feeling crummy during an illness is partly the result of chemicals produced by infected tissue. Several of these compounds, such as prostaglandins, are known to trigger sickness behaviors. (Drugs such as ibuprofen work by blocking prostaglandin production.)

But it’s often unclear exactly how these chemicals communicate with the brain, says Stephen Liberles, a molecular neuroscientist at Harvard Medical School. “Surprisingly little is understood about how the brain becomes aware that there’s an infection in the body.”

In the new study, Liberles, postdoc Na-Ryum Bin, and colleagues focused on influenza, which infects the body’s airways. Previous research hinted that a type of prostaglandin made in response to viral infection called PGE2 could travel via the blood to interact with cells in the brain. But when the researchers infected mice that had been genetically engineered to lack receptors for PGE2 in the central nervous system, the animals still acted sick—avoiding eating and drinking, and moving around less than normal.

This suggested PGE2 was instead being detected by the peripheral nervous system, which consists of the neurons outside the brain and spinal cord. To narrow down where in the body this detection was happening, the team combined various genetic tools to create mouse strains with progressively smaller sets of PGE2 receptors disabled. Eventually, they homed in on a cluster of neurons in the back of the throat that connects the upper airways to the brain. Mice lacking receptors in these cells didn’t act sick when they got flu. The team achieved the same effect in normal mice by cutting through the nerve, or by giving the animals ibuprofen.

A cluster of neurons (red) in the back of the throats of mice detect a compound called PGE2 (in blue areas) that’s produced in response to viral infections.Na-Ryum Bin

The findings, published today in Nature, point to a specific detection system for respiratory infections. This system could have several benefits, Liberles says. Prostaglandins are fragile and might not make it all the way to the brain via the blood, so having neurons sense them where they are produced could be more reliable. The system also provides the brain important information about where the infection is, perhaps setting up a site-specific response, such as coughing.

The discovery of this peripheral pathway “redefines our understanding of how influenza virus infection affects the nervous system to cause sickness behavior,” Elia Tait Wojno, an immunologist at the University of Washington, Seattle, writes in an email. Tiny molecules such as prostaglandins are “notoriously difficult to study,” she adds, praising the researchers’ use of “cutting-edge genetic tools” to narrow in on the mechanism.

Interestingly, blocking the PGE2 pathway was less effective at eliminating sickness behavior during later stages of infection, Ilanges notes. This perhaps suggests a different pathway makes mice act sick once disease has progressed from the upper airways into the lungs.

The team also found disabling the PGE2-detecting neurons boosted mice’s chances of surviving. This jibes with other studies showing that blocking PGE2 synthesis improves survival in mice with flu, but it raises the question of why such a pathway evolved in the first place.

One possible explanation: Although sickness behavior makes mice more vulnerable to influenza, it may protect them against other infections. For example, some studies show mice with bacterial sepsis are less likely to survive if they eat more food—probably because the bacteria tap the animal’s blood sugars for fuel. In that instance, a loss of appetite is a good thing, Liberles says.

Or perhaps the behavior evolved not because it helps sick animals directly, but because it protects their relatives from infection by reducing the sick mouse’s social interaction, he notes.

It’s unclear whether the throat’s prostaglandin-detecting nerve cells are relaying information about bacteria and viruses other than influenza. “It’ll be really important to [explore] other types of infection,” Ilanges says.

The researchers plan to do just that, as well as look for infection-detecting neurons in other parts of the body such as the gut, says Liberles, who consults for the gut-brain research company Kallyope. “These are all really exciting questions moving forward.”

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