Epigenetic kill switch improves defenses against infection — Zoo House News

Epigenetic kill switch improves defenses against infection — Zoo House News

  • Science
  • December 12, 2022
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In the case of infections, the blood-forming system switches from normal to emergency mode. This improves the defense against pathogens. Scientists at the German Cancer Research Center (DKFZ) have now found an epigenetic switch in mouse blood stem cells and progenitor cells that can trigger the switch from one mode to the other.

If the emergency hematopoiesis program starts in the body, this signals an alarm state of the immune system and serves two purposes: Compared to hematopoiesis in “normal mode”, the emergency program leads to an increased supply of immune cells used up during infections or inflammations. In addition, the emergency program puts the entire immune system into pre-activation, which helps to eliminate infections more quickly.

Characteristic of the emergency program are, for example, an increased rate of division of blood stem cells and a shift in the balance of mature white blood cells in favor of myeloid cells (macrophages and granulocytes). Normally, the emergency program is triggered by typical molecular components of pathogens or by inflammatory messengers such as certain interferons.

But what happens in the blood stem cells and progenitor cells? Is there a cell phone switch that triggers the emergency program? Scientists working with Nikolaus Dietlein and Hans-Reimer Rodewald from the German Cancer Research Center (DKFZ) are targeting a specific epigenetic modification, H2Bub1 for short. It is involved in turning on genes that are activated by interferon following viral infection and that are important in fighting off infection. The modification that adheres to the packaging proteins of the DNA, the histones, is removed again by the enzyme USP22.

Could H2Bub1 and USP22 be the switch that triggers the emergency response program in the blood stem cell? The researchers led by Rodewald investigated this in mice in whose blood stem cells USP22 was genetically switched off. In these animals, the emergency program of hematopoiesis, with all its essential features, proceeded without detectable infection or elevated levels of interferon.

The genetically modified animals were better able to fight off an infection with the bacterium Listeria monocytogenes than normal mice. Also, important scavenger cells in their blood, neutrophils, were more successful at engulfing bacteria.

As expected, the genetic material in the blood cells of the genetically modified animals also showed significantly more of the epigenetic H2Bub1 changes. “The increased H2Bub1 level seems to be the alarm button that puts the immune system on standby. In particular, this puts the innate immune system, which is particularly important when you first come into contact with a pathogen, in an increased state of defense,” says Nikolaus Dietlein, first author of the current publication. USP22 removing the H2Bub1 modification stops the alarm in normal animals.

H2Bub1 and USP22 are also found in human cells and, according to current research, fulfill functions comparable to those in mice. Hans-Reimer Rodewald says: “We were able to show in mice that an epigenetic modification improves the defense against infection. However, how the loss of USP22 affects human hematopoietic stem and progenitor cells is still unknown and will now be studied. USP22 through drugs could potentially one day help improve immune defenses against pathogens. So far, however, this is still unproven and needs to be tested in further studies.”

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