Humans breathe in somewhere between 1,000 and 10 billion watts on an average day—just think of the days after a catastrophic flood or a Category 5 hurricane, when volcanic eruptions can occur. Each of those teenagers has the ability to enter the moisture, our lungs. There they can release fungal spores that grow like kudzu, attacking and robbing our organs, slowly draining our life like smoke bursting from our veins.
Fortunately, our immune systems protect most of us from this painful death. But they don’t get away with bloody, daily mushroom slaughter—no, they use a much more dignified defense, according to a new study.
In the lung, immune cells get stimulated with fungal spores, then trick them into pushing their own destruction buttonsInvestigators reported Thursday Knowledge. When researchers used genetic engineering to overcome the spore’s self-destructive system, the immune cells in the mice were unable to stop the fungus from invading.
The findings suggest that our immune systems use clever manipulation to “keep the immune system sterilizing in the lung,” according to the researchers, led by epidemiologist Tobias Hohl of Memorial Sloan Kettering Cancer Center.
But not all of us are so lucky. People whose immune systems are compromised from drugs, other infections, or immune disorders can’t always fight off the fungus. For those issues, researchers hope that new understanding of capital defenses “may inform new strategies for therapeutic intervention in vulnerable patient groups.”
To differentiate the fungal attack, the researchers looked closely at how mammalian immune cells interact with the spores. Aspergillus fumigatus, the most common cause of influenza worldwide. They note that a special interaction seems to occur between the spores and neutrophils, highly mobile immune cells that rush to the site of an attack or injury to go up the pathogens like Pac-Man and pump out signals. a chemical that increases inflammatory responses.
In this case, the neutrophils are killing—technically, phagocytosing—them A. fumigatus spores, but they do not kill them individually. Instead, they seem to be dying a programmed cell death—that is, a form of self-destruction or apoptosis.
Programmed cell death (PCD) is a common process in animals, plants, and fungi, in which a cell kills itself for the greater good. The self-destruct button is hit in situations such as severe stress or when there is irreversible damage to the DNA. If a cell loses the ability to make PCD, it can be considered “immortal.” Loss of PCD is a hallmark of cancer cells and tumor growth.
To confirm that neutrophils cause PCD in spores, the researchers turned to genetic engineering. They took out a gene in the spore DNA that was similar to the human one, known to encode a protein called Survivin. In human cells, Survivin becomes PCD. So the researchers engineered the spores to produce a protein similar to Survivin, making it much harder for them to destroy themselves.
In mice, spores loaded with Survivin did not die as normal, and they were lethal to mice—killing nearly three times the number of animals in one experiment. When the researchers took a closer look, they found that Survivin-enriched spores caused “massive tissue destruction.” But when the researchers added a drug that blocks Survivin, the spores returned to die in neutrophils and did not cause the deadly disease.
So how do neutrophils get the spores to commit suicide? In the lab, the researchers noticed that the spores with Survivin were better at surviving oxidative stress than normal. This gave the researchers the idea that the immune cells may not be using an enzyme called NADPH oxidase to trick the spores into thinking they have disappeared in the stress area. That thinking falls in line with the fact that people with a genetic defect in their NADPH oxidase gene have a higher risk of having a fatal fungal infection during their lifetime.
Indeed, mice lacking the enzyme were almost completely protected against the spores, regardless of whether the spores contained a certain amount of Survivin. In other words, without the stress enzyme, the neutrophils cannot turn the spores into suicide.
Together, the findings suggest that our immune systems have a subtle mechanism for protecting us from fungi. If we can consider substance abuse equally in the self-destructive system, researchers hope that we can better protect vulnerable patients one day.
Knowledge2017. DOI: 10.1126 / science.aan0365 (About DOIs).