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One Way Your Immune System Fights Off Bacteria: Cell Suicide

Desperate plagues call for desperate measures.
Image: salmonella bacteria/Wiki

Imagine the moments before some battle of the American Civil War, with wave after wave of blue and grey-suited infantrymen stacked against each other in orderly lines, rifles ready. The lead officers, instead of yelling "charge!," instead turn back toward their soldiers, pull out their swords and impale themselves, falling dead. That's the signal the troops were waiting for: suicide. The battle commences like normal. Humans have a wide variety of vastly more preferable modes of interpersonal communication, but at the cellular level, what you find is a whole lot of just making do. Some of it winds up being pretty clever, like quorum sensing in bacteria, but in the case of human immune cells in the presence of dangerous bacteria, information may take the form of death. This is according to a study out this week in the Proceedings of the National Academy of Sciences describing a beneficial behavior utilizing the variety of programmed cell death known as pyroptosis. First off, death isn't exactly the immune cells' first choice of communication. There are a few more-savvy communication methods they employ first, such as molecular signalling via cytokines, the intercellular carriers of very tiny bits of chemical information. Receptors on other immune cells bind to the cytokines and the resulting collective behavior is to form a cellular blockade against the harmful pathogen. Sometimes this doesn't work though. The bacteria studied in the PNAS report, Yersinia (the genus that boasts the plague, among other harmful species), produces a protein called YopJ. This protein is useful for blocking the signalling pathway used by immune cells to move their cytokine messengers around. And with this pathway blocked, the Yersinia are free to infect host cells and eventually kill them off. This is bad news for you, the organism, as it's one mechanism by which bacteria chew through your immune system and, eventually, you. Immune cells pretty much exist to keep that from happening, and, according to the report, have one peculiar last resort. When the bacteria unleash their signalling blockade, they trigger the production of an enzyme called caspase-1 by immune cells. This enzyme is another signalling molecule and it has the effect of triggering the process of pyroptosis. This mechanism is one of a few varieties of programmed cell death and its role is a bit more specialized than its relatives. The effect of this particular death is effectively to act as an antibiotic, as the self-destruct cascade releases cytokines, the warning messages above, and it alerts other nearby immune cells that the shit is going down and they need to march on an invading microorganism at once. The result is inflammation. It may appear that the invading bacteria are just telling cells to kill themselves because that's what they want, but it doesn't seem to be the case. The researchers worked with mice engineered to lack caspase-1 (by removing another, related enzyme needed to produce it) and found that in the absence of this self-destruct signal, the mice were dramatically more susceptible to infection. "One thing that was really surprising was that even though these mice had very high bacterial burdens, their cells were not capable of producing inflammatory cytokines," senior author Igor E. Brodsky notes in a press release. "What that suggests to us is that the activation of this cell death pathway is a potential way for cells that are infected to alert uninfected cells.” One can imagine that the bacteria’s strategy of triggering of caspase-1 release was once a successful offensive strategy, but that the immune cells over time learned (via adaptation/selection) to use that signal instead to trigger a beneficial variety of cell death, subverting the bacteria nicely. It’s expected that other forms of bacteria share a similar failed tactic and, ultimately, it’s another fine example of nature being clever, but one that may have future ramifications for our own stalemated fight against rapidly evolving harmful bacteria.