Researchers have discovered the lungs communicate directly with the brain when there is an infection. Findings show the brain plays a critical role in triggering the symptoms of sickness, which may change the way we treat respiratory infections and chronic conditions.  

“The lungs are using the same sensors and neurons in the pain pathway to let the brain know there’s an infection,” says the senior author on the study. “The brain prompts the symptoms associated with sickness; that overall feeling of being unwell, feeling tired and loosing your appetite. The discovery indicates we may have to treat the nervous system as well as the infection.”

Prior to this study, conducted in mice, it was thought infections in the lungs and pneumonia induce inflammatory molecules that eventually made their way to the brain through the blood stream. Sickness was thought to be a consequence of the immune system kicking into action. However, findings reveal that sickness results from nervous system activation in the lung.

Understanding the lung-brain dialogue is important for treatment because bacteria that cause lung infections can produce a biofilm, a coating to surround themselves so the nervous system can’t see them. That allows the bug to hide out in the lungs for a long time, which may shed light across diverse serious lung infections that are less symptomatic.

“We would have patients whose oxygen levels were extremely low and x-rays confirmed they may need to be put on life support. Yet, when I went to see the patient, they would say I feel fine,” says the author. “These people were experiencing limited sickness symptoms even though the virus was aggressively damaging their lungs.”

The author says understanding the lung brain communication pathways may also have broad implications for people with chronic lung infections like cystic fibrosis (CF). Many people with CF have a biofilm bacterium in their lungs and are asymptomatic. They feel okay, but then have a flare where they can become very ill. The reason for the flare can’t always be traced.  

"It is possible the flare is also neurological that these people live asymptomatically because bacteria are hiding out,” says the author.

The findings, published in Cell, are the work of an interdisciplinary team including experts in neurobiology, microbiology, immunology, and infectious disease.

Gram-negative bacteria produce exopolysaccharide (EPS) that provides microbial protection; however, the impact of EPS on sickness remains uncertain. Using genome-engineered Pseudomonas aeruginosa (P. aeruginosa) strains, the authors compared EPS-producers versus non-producers and a virulent Escherichia coli (E. coli) lung infection model in male and female mice.

EPS-negative P. aeruginosa and virulent E. coli infection caused severe sickness, behavioral alterations, inflammation, and hypothermia mediated by TLR4 detection of the exposed lipopolysaccharide (LPS) in lung TRPV1+ sensory neurons. However, inflammation did not account for sickness.

Stimulation of lung nociceptors induced acute stress responses in the paraventricular hypothalamic nuclei by activating corticotropin-releasing hormone neurons responsible for sickness behavior and hypothermia. 

“Physician specialties are usually based on individual organs, with pulmonologists caring for the lungs and neurologists caring for the brain. Our study shows the lung is altering the brain and the brain is altering the organ. This intersection of communication is a different way of thinking about disease,” says the author. “It’s all connected to the brain and there are probably even more complex circuits that are happening. We can now think about targeting neurocircuitry along with antibiotics to deal with infections and the sickness they cause.”

The researchers add there was one more unique finding. Male mice were much sicker than the females even though they had the same bacterial infection. Researchers found that male sickness was more dependent on neuronal communications then females. The author says this finding could lend credibility to the so-called “man flu”, a colloquial term where men are thought to wildly exaggerate sickness due to respiratory infections. Turns out they may not be exaggerating, after all.  

https://www.cell.com/cell/abstract/S0092-8674(24)00249-6

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