AsianScientist (Aug. 6, 2020) – To avoid immune defences, the bacteria Burkholderia pseudomallei causes the fusion of infected cells. However, this fusion itself can trigger the immune system, leading to the self-destruction of the abnormal fused cells. These findings, by researchers at the National University of Singapore (NUS), were published in the Proceedings of the National Academy of Sciences.
Though most people might not have heard about melioidosis, the tropical disease kills an estimated 90,000 people a year—four times the number of people that die from dengue. Melioidosis is caused by the soil bacteria B. pseudomallei, which is unusually hardy and resistant to many antibiotics.
One reason that B. pseudomallei is difficult to treat is that it can spread directly from cell to cell, thereby avoiding immune defences targeted outside the cell. In the present study, researchers led by Associate Professor Gan Yunn Hwen at NUS show how the immune system has found an ingenious workaround to detect B. pseudomallei: by sensing the fusion of cells rather than the bacteria itself.
B. pseudomallei is known to cause cell fusion through a complex of proteins known as type VI secretion system 5 (T6SS5). Instead of using T6SS5, the researchers mimicked cell fusion using polyethylene glycol, thereby simulating cell fusion without interference from bacterial nucleic acids which are typically injected by T6SS5. To their surprise, this simulated cell fusion was enough to activate the innate immune system, specifically the release of type 1 interferons.
The researchers also found that the giant multi-nucleated cells formed through cell fusion did not behave like normal cells. Firstly, they started to divide but could not complete the process. Secondly, the DNA in the giant cells was damaged, making it more unstable. These are ripe conditions for the cells to transform into cancer cells.
One of the hallmarks of damaged, unstable DNA is the presence of micronuclei, which form when bits of DNA fail to segregate properly during cell division. When these micronuclei rupture—which they are prone to do—the DNA is made accessible to factors in the cytosol. Gan and her team observed micronuclei in the giant cells and a corresponding activation of the cGAS-STING pathway of the immune system, which senses the out-of-place DNA and is known to lead to type 1 IFN signaling.
However, under the onslaught of extensive cell fusion, the activated cGAS-STING pathway turns on an unusual death program known as autophagy instead of producing type 1 IFN, which ultimately causes these abnormal giant cells to self-destruct. Since unnatural cell fusion is often accompanied with DNA damage and instability, the killing mechanism could be a powerful way to destroy cells before they become cancerous.
These findings add to our understanding of how the immune system resists abnormally fused cells, whether a result of infections or through exposure to chemicals. The study also demonstrates that abnormal cell fusion is a danger signal that can be sensed by the immune system.
“Our microbial adversaries are often our best teachers. Learning how to cure and control infections are critically important,” Gan said. “However, understanding the interactions between pathogen and host is equally important, because it allows us to discover what our immune system is capable or incapable of, and these fundamental discoveries can give us new perspectives in maintaining health and treating disease.”
The article can be found at: Ku et al. (2020) Bacterial-induced Cell Fusion is a Danger Signal Triggering cGAS–STING Pathway via Micronuclei Formation.
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Source: National University of Singapore; Photo: Gan Yunn Hwen.
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