Decoding a protein to fend off sepsis

From Orlando, Fla., at a meeting of the American Society of Hematology

Sepsis is a lethal blood disorder that typically arises from bacterial infections. It’s marked by organ damage caused by inflammation and blood vessel leakage. A synthetic version of activated protein C (ACP) is the sole drug approved to specifically attack sepsis, but it only slightly reduces the risk of death. Scientists had suggested that APC works by protecting healthy cells from dying and had found it to have anticoagulant effects.

A study in mice now finds that the anticoagulant property isn’t APC’s key attribute—in fact, it might even be a shortcoming. Instead, APC’s value stems from its ability to attach to two proteins on the surface of cells. By binding to these two receptors, APC inhibits a death signal in a cell, says biologist Harmut Weiler of the BloodCenter of Wisconsin in Milwaukee.

Weiler notes that the two affected receptors are commonly found on cells that make up blood vessels. He and his colleagues report that in mice with sepsis treated with APC, animals that lacked the two receptors were more likely to die than were mice that had the receptors.

“This is a trailblazing study,” says Khanti R. Rai, a physician at the Long Island Jewish Medical Center in New Hyde Park, N.Y. It argues for maintaining the integrity of vessel walls in fighting sepsis, he says.

Weiler’s group also discovered a danger of APC’s anticoagulant effect. Mice infected with Staphylococcus aureus all died from sepsis, despite treatment with standard APC. But when given APC that had been altered to lack the anticoagulant stimulus, nearly all the mice survived.

The findings could eventually lead to a modified, more potent version of APC, Weiler says. An APC molecule without anticoagulant properties might enable doctors to prescribe larger doses, he says.