Many organisms react to the smell of deadly pathogens by reflexively avoiding them. But a recent study from the University of California, Berkeley, shows that the nematode C. elegans It also reacts to the smell of pathogenic bacteria by preparing its intestinal cells to resist a possible attack.
As in humans, the intestines of nematodes are a common target for disease-causing bacteria. The nematode reacts by destroying iron-containing organelles called mitochondria, which produce the cell’s energy, to protect this critical element from iron-stealing bacteria. Iron is a key catalyst in many enzymatic reactions in cells, in particular the generation of the body’s energy currency, ATP (adenosine triphosphate).
The presence in C. elegans The results of this protective response to odors produced by microbes suggest that gut cells in other organisms, including mammals, may also retain the ability to respond protectively to the odor of pathogens, said senior study author Andrew Dillin, a professor of molecular and cellular biology at UC Berkeley and a Howard Hughes Medical Institute (HHMI) investigator.
“Is there really an odor that emanates from pathogens that we can perceive and that helps us fight an infection?” he said. “We have been trying to demonstrate this in mice. If we can discover that humans smell a pathogen and therefore protect themselves, we can imagine in the future something like a perfume that protects them from pathogens.”
So far, however, there is only evidence of this response in C. elegansThe new finding is a surprise, however, considering that the nematode is one of the most studied organisms in the laboratory. Biologists have counted and tracked every cell in the organism from embryo to death.
“The novelty is that C. elegans “Smell prepares for a pathogen before it even encounters it,” said Julian Dishart, who recently received his PhD from UC Berkeley and is the first author on the study. “There’s also evidence that there’s probably a lot more going on than just this mitochondrial response — that there might be a more generalized immune response to simply smelling bacterial odors. Because smell is conserved across animals, in terms of regulating physiology and metabolism, I think it’s entirely possible that smell is doing something similar in mammals to what it’s doing in humans.” C. elegans.”
The work was published on June 21 in the journal Scientific advances.
Mitochondria communicate with each other
Dillin is a pioneer in the study of how stress in the nervous system triggers protective responses in cells, in particular, the activation of a set of genes that stabilize proteins produced in the endoplasmic reticulum. This activation, called the unfolded protein response (UPR), is “like a first aid kit for mitochondria,” he said.
Mitochondria are not only the powerhouses of the cell, burning nutrients for energy, but they also play a key role in signaling, cell death, and growth.
Dillin has shown that errors in the UPR network can lead to disease and aging, and that mitochondrial stress in one cell is communicated to mitochondria in cells throughout the body.
However, a key piece of the puzzle was missing: If the nervous system can communicate stress through a network of neurons to the cells that do the daily work of generating and metabolizing proteins, what elements of the environment trigger the nervous system?
“Our nervous system evolved to pick up signals from the environment and create homeostasis for the entire organism,” Dillin said. “Julian discovered that olfactory neurons pick up environmental cues and what types of odors from pathogens trigger this response.”
Previous work in Dillin’s lab demonstrated the importance of smell in mammalian metabolism. When mice were deprived of smell, he found, they gained less weight while eating the same amount of food as normal mice. Dillin and Dishart suspect that the smell of food may trigger a protective response, like the response to pathogens, in order to prepare the gut for the damaging effects of ingesting foreign substances and converting that food into fuel.
“Surviving infections was the most important thing we did from an evolutionary standpoint,” Dillin said. “And the most risky and demanding thing we do every day is eat, because pathogens are going to be present in our food.”
“When we eat, we also feel incredibly stressed, because the body is metabolizing food but also generating ATP in the mitochondria from the nutrients that it takes in. And that generation of ATP causes a byproduct called reactive oxygen species, which is very damaging to cells,” Dishart said. “Cells have to deal with this increased existence of reactive oxygen species. So maybe smelling food can prepare us to deal with that increased load of reactive oxygen species.”
Dillin further speculates that the sensitivity of mitochondria to the scent of pathogenic bacteria may be a holdover from a time when mitochondria were free-living bacteria, before they were incorporated into other cells as powerhouses to become eukaryotes about 2 billion years ago. Eukaryotes eventually evolved into multicellular organisms with differentiated organs, called metazoans, like animals and humans.
“There is a lot of evidence that bacteria sense their environment in some way, although it is not always clear how they do this. These mitochondria have retained an aspect of that after being taken over by metazoans,” he said.
In his experiments with C. elegansDishart discovered that the smell of pathogens triggers an inhibitory response, which sends a signal to the rest of the body. This became clear when he removed the worm’s olfactory neurons and found that all peripheral cells, but mainly those in the gut, showed the stress response typical of mitochondria that are threatened. This study and others also showed that serotonin is a key neurotransmitter that communicates this information throughout the body.
Dillin and his lab colleagues are tracing the neural circuits that run from olfactory neurons to peripheral cells and the neurotransmitters involved in the pathway. And he’s looking for a similar answer in mice.
“I always hate it when I get sick. I think, ‘Body, why didn’t you prepare better for this?’ It seems really stupid to me that you activate response mechanisms only once you’re infected,” Dillin said. “If there are earlier detection mechanisms to increase our chances of survival, I think that’s a huge evolutionary achievement. And if we could harness that biomedically, that would be pretty incredible.”
Other authors on the UC Berkeley paper include Corinne Pender, Koning Shen, Hanlin Zhang, Megan Ly and Madison Webb. The work is supported by HHMI and the National Institutes of Health (R01ES021667, F32AG065381, K99AG071935).