For many of us, a bad smell is a simple warning: rotten food, a stinky diaper, or a trash can left too long in the sun. We might pinch our noses and walk away, but a groundbreaking new study reveals that your sense of smell may be doing far more than just helping you avoid a noxious odor. Researchers at the University of California, Berkeley, have discovered that the nose, a surprisingly ancient and powerful sensory organ, can act as an early warning system, priming the body to fight off a bacterial infection before it even has a chance to take hold.
The idea that a distant, non-immune organ like the nose can sense danger and prepare the rest of the body for a fight is a huge evolutionary win. As the senior author of the study, Dr. Andrew Dillin, puts it: “If we can actually figure out that humans smell a pathogen and subsequently protect themselves, you can envision down the road something like a pathogen-protecting perfume.”
Your Nose Can Prepare Your Body for Sickness
The researchers focused on a single pair of neurons called AWC neurons. These neurons are unique because they are “tonically active” in the absence of any smell, meaning they are always sending signals. When they detect a specific odorant—a molecule that produces a scent—they become silenced, or “turned off.” This silencing is what triggers the defensive response.
To investigate the role of these neurons, the researchers used a few primary methods. In one experiment, they used genetic ablation to permanently turn off or destroy the AWC neurons. By doing this, they could see what happened to the worm’s body when this specific signaling pathway was removed. They then exposed the worms to the pathogenic bacteria Pseudomonas aeruginosa, a common threat to both worms and humans. The worms with ablated AWC neurons were significantly more resistant to the infection than the normal worms.
The second method involved exposing normal worms to a specific bacterial odorant called 2,3-pentanedione (2,3-pent). This is a smell produced by P. aeruginosa that normally silences the AWC neurons. The results were the same: the worms exposed to the odor became more resistant to the bacteria.
How a Worm Prepares for War
What exactly happens inside the worm’s body when its AWC neurons are silenced? The study found that this “preparatory” response works by modifying mitochondria, the tiny organelles inside our cells that act like power plants, generating the energy our bodies need to function. The key finding is that the worms’ bodies actively reduce the number of mitochondria and also decrease their function, a process known as mitophagy.
This might seem a bit odd. Why would an organism purposefully lower its energy output right before a battle? The researchers found that the answer lies in the bacteria themselves. Many bacteria, including P. aeruginosa, are masters at stealing iron, a crucial component found in mitochondria. By pre-emptively destroying or reducing the number of these iron-rich powerhouses, the worm makes itself less of a feast for the bacteria. The body is sacrificing a power source to deny the enemy a valuable resource.
The study also revealed the specific molecular players involved in this process. It found that the reduction in mitochondria was dependent on serotonin signaling. The same serotonin that’s often called the “feel-good” hormone in humans is a key communicator in this defensive pathway. When the AWC neurons are silenced, it triggers an intermediary neuron to release serotonin, which then travels to the peripheral cells—in this case, primarily the gut cells—and signals them to get rid of their mitochondria.
Another crucial component identified was a protein called parkin. This is an important piece of the puzzle because parkin is a key player in the process of mitophagy. The fact that the worm’s ability to resist the infection was fully dependent on parkin highlights how crucial this process is to the overall defense strategy.
What This Means for Humans
While the study was conducted exclusively on the roundworm C. elegans, the findings offer a fascinating glimpse into the deep connections between our senses and our immune systems. The research indicates that our brains and their senses, which we often see as separate from the rest of the body, are in constant conversation with our internal organs. This is not a passive relationship but an active, anticipatory one. The researchers believe that this evolved as a way to prepare the organism for the metabolic stress of either eating, which involves a lot of work to break down food and absorb nutrients, or to withstand a pathogenic infection from contaminated food.
Paper Summary
Methodology
Researchers used the nematode Caenorhabditis elegans as a model organism to study how the sense of smell can regulate the body’s internal functions. They focused on a specific pair of olfactory neurons called AWC neurons. The researchers used genetic ablation, a bacterial odorant, and a genetic system using histamine to silence these neurons. They then measured the worm’s survival rate when exposed to pathogenic bacteria, changes in mitochondrial function, and the amount of mitochondrial DNA.
Results
The study found that silencing the AWC olfactory neurons led to a stress response that reduced mitochondrial function and the number of mitochondria throughout the worm’s body. This preparatory response made the worms more resistant to infection from the pathogenic bacteria Pseudomonas aeruginosa. The researchers determined that this protective effect was dependent on serotonin signaling and a protein called parkin, which is responsible for the destruction of mitochondria.
Limitations
The study was conducted exclusively on the roundworm C. elegans. While the researchers did a follow-up experiment using human cells, the protective response has only been fully demonstrated in the worm. Future research in more complex organisms is needed to determine if this same mechanism exists in humans.
Funding and Disclosures
This research was supported by grants from the National Institutes of Health (NIH), the Larry L. Hillblom Foundation, the Glenn Foundation for Medical Research, the National Science Foundation (NSF), and the Howard Hughes Medical Institute (HHMI).
Paper Publication Info
The study is titled “Olfaction regulates peripheral mitophagy and mitochondrial function”. The paper was published in Science Advances on June 21, 2024. The authors are Julian G. Dishart, Corinne L. Pender, Koning Shen, Hanlin Zhang, Megan Ly, Madison B. Webb, and Andrew Dillin.