When the bee stings

HHMI Bulletin | Spring 2013
By Kelli Whitlock Burton

The immune system is hailed for detecting and fighting bacterial and viral infections. But what of the system’s equally important response to bee stings and snake bites? Spiders, bees, snakes, and scorpions inject their victims with a toxic cocktail of proteins that cause an inflammatory response—pain, swelling, redness—and severe tissue damage. Just how the immune system detects and responds to venom is a mystery. New studies by HHMI investigator Ruslan Medzhitov suggest that clues may lie in the actions of a protein complex called the inflammasome.

“Much of our understanding of the immune system is based on its reaction to microbial pathogens,” Medzhitov says. “But venoms don’t follow the same rules of immune recognition and response.”

Although the makeup of venom differs from species to species, one common denominator is a group of proteins that damage the cell membrane. Medzhitov and his Yale University postdoctoral fellow Noah Palm looked at inflammasomes, multiprotein immune complexes that react to membrane damage.

To study the inflammasome’s role, the pair injected two groups of mice with bee venom. Half the mice were normal while the other half lacked caspase-1—an enzyme found in inflammasomes. In the normal mice, the toxin activated an inflammasome that turns on the inflammatory system, a protective response that promotes tissue repair. The caspase-1-deficient mice had less inflammation than the normal group, but they experienced far more tissue damage. This result points to a key role for inflammasomes in detecting venom, says Medzhitov, who published the findings January 29, 2013, in Proceedings of the National Academy of Sciences.

“We found that instead of inflammation passively following tissue damage, inflammation is actively engaged by a sensor and that sensor is the inflammasome,” he says. “This also demonstrates very clearly the protective effect of inflammation.”

Now that Medzhitov has identified the sensor involved in venom-induced inflammation, he wants to find the trigger in another venom response. Around 2 percent of Americans have severe, life-threatening allergic reactions to bee stings, a malady that kills about 100 people a year in the United States. Pinpointing the sensor involved in venom allergies would be a key first step in preventing those deaths.