The proteins that keep DNA wound tightly inside a cell's nucleus—called histones—have no place outside the cell. New research suggests that when they land in the bloodstream, they encourage sepsis, the potentially deadly response of the immune system to severe infection. Destabilizing histones that escape the cell can halt the spiral of events that make sepsis lethal.
HHMI investigator Charles T. Esmon's lab group at the Oklahoma Medical Research Foundation previously showed that a compound called activated protein C (APC) could block sepsis. Although a commercial drug, Xigris, was developed from APC, its mechanism remained unclear, and it didn't work in all cases. Esmon was determined to further unravel the molecular basis of sepsis.
The idea that histones might play a role in sepsis came serendipitously. Jun Xu, a postdoctoral fellow in Esmon's lab noticed histones in cultures where macrophages—a type of immune cell—had become inflamed and cleaved and their toxic activities neutralized by APC.
“People had seen histones in the blood before,” says Esmon, “but assumed they leaked out of cells as a side effect of the major damage caused by sepsis. No one ever guessed they had a more central role.”
To determine whether the chopped up histones were more directly related to sepsis, the researchers exposed blood vessel cells—normally damaged during sepsis—to histones and to histone fragments. The intact histones killed cells while the histone fragments did not.
Esmon's team also looked at mice, baboons, and humans with sepsis—they all had free-floating histones in their blood. When the researchers gave a histone-blocking protein to septic mice, which were expected to die, many of the mice survived.
The data, published in the November 2009 issue of Nature Medicine, suggest a new theory on sepsis: Initial cell damage, from widespread inflammation due to an infection, lets histones leak into the bloodstream. These histones kill more cells, which release more histones, in a vicious cycle. APC, scientists now know, cleaves those histones to stop sepsis. The severe side effects of APC, however, make it a last resort drug. Other histone blockers, which may cause fewer side effects, can now be tested on sepsis.