Unusual Allies: Vagus Nerve Cells Emerge as Defenders Against Flu Damage

“Flu infections are highly variable in severity and there is a need to understand why certain groups of people, such as the elderly, experience worse disease,” said study first author Nicole Almanzar, a doctoral student in the Chiu Lab. “Our study demonstrates that the nervous system is actively involved in regulating the response of the lungs to infection, offering a new perspective on viral infections that could help explain why particular factors increase risk of severe infections.”

The new study illuminates the complex interaction between body and brain and adds to a growing body of research showing that the nervous and immune systems engage in highly orchestrated crosstalk during infection to modulate body defenses.

Previous research led by Chiu has revealed the intricate interplay between the two systems in bacterial pneumonia, flesh-eating disease, meningitis, pain, and itch.

One of Chiu’s earlier studies found that during bacterial infections of the lung, the same set of vagal nerve neurons suppressed the immune defenses. In the new study, however, the immune-taming function of these cells worked to shield the lung from excessive damage during viral infection.

“Context clearly matters,” Chiu said.

Disabling the neurons worsened flu damage in the lungs

In a set of experiments, researchers exposed a group of mice with genetically disabled or chemically silenced TRPV1 neurons to influenza A virus. Mice without these nerve cells fared notably worse than mice with functioning TRPV1 cells. Even though the overall amount of virus in the lungs was the same in both groups, mice lacking TRPV1 neurons suffered more severe lung pathology, higher levels of harmful inflammation, and lower survival rates. Interestingly, Almanzar noted, even though the overall viral load remained the same, the spread of the virus within the lobes of the lungs was more pronounced in mice without these protective neurons.

The researchers also found that the absence of TRPV1 neurons altered the lung’s immune landscape. The lungs of mice lacking these neurons had an overabundance of neutrophils and macrophages — two types of immune cells that, in excess, can worsen tissue damage. At the same time, interferon signaling — one of the body’s most important viral-defense pathways — was seriously impaired in these immune cells.

In another experiment, the researchers used an antibody to deplete inflammation-driving cells in flu-infected mice lacking TRPV1 neurons. These animals had notably better survival than untreated mice lacking these protective neurons. The observation further underscores how nerve cells help prevent harmful immune reactions that can sometimes be more dangerous than the virus itself.

The researchers noted that they do not yet know precisely how TRPV1 neurons restrain the march of inflammatory cells at the molecular level — a question they plan to explore in subsequent work.

“The vagus nerve is powerfully controlling inflammation, but how it does so remains a mystery to be solved,” Chiu said. “But we’re excited that it plays such a strong role in viral infections.”

Harnessing the immune brake for therapy

Moving forward, this insight opens the door to exciting new avenues for therapy. Instead of only targeting the flu virus or dampening immune activity, the research team said, future treatments could mimic the function of nerve cells to ensure the delicate balance between protective and damaging immune responses is not thrown off.

The idea is not that far-fetched, the researchers said, noting that the FDA recently approved a therapy for rheumatoid arthritis by vagus nerve stimulation.

“Imagine if you could harness this brake to control inflammation in the lungs and beyond,” Chiu said. “By stimulating related circuits where the vagus nerve shuts down immune cells, one could envision treating immune-mediated dysfunction of many kinds, including that caused by viral infections.”