Disabling Key Protein May Give Physicians Time To Treat Pneumonic Plague

The deadly attack of the bacterium that causes pneumonic plague is significantly slowed when it can't make use of a key protein, scientists at Washington University School of Medicine in St. Louis report in Science.

Speed is a primary concern in pneumonic plague, which kills in three to four days and potentially could be used in a terrorist attack. The bacterium that causes plague, Yersinia pestis, is vulnerable to antibiotics, but by the time an unusual infection becomes evident, Yersinia often has gained an unbeatable upper hand.

"By the time most doctors recognize an infection as plague, rather than the flu, it's already too late to begin antibiotic treatment," says senior author William Goldman, Ph.D., professor of molecular microbiology. "That makes pneumonic plague a concern both because of its rare natural outbreaks, one of which began in the Congo in 2005, and because of its potential use as a bioweapon."

Yersinia is best known for causing the Black Death in the Middle Ages in Europe, when historians estimate it killed a third or more of the population. Depending on how Yersinia is introduced, the versatile pathogen can modify itself to infect the lungs (pneumonic plague), the lymph glands (bubonic plague), or the bloodstream and organs (septicemic plague). Bubonic plague was spread by bites from infected fleas; pneumonic plague can spread through droplets of moisture expelled by coughing and sneezing.

With pilot project funding from the Midwest Regional Center for Excellence in Biodefense and Emerging Infectious Diseases Research, Wyndham Lathem, Ph.D., a postdoctoral fellow in Goldman's laboratory, developed a mouse model of pneumonic plague and showed that it had many similarities to human infection. In mice, pneumonic plague causes the lungs to fill up with a fluid composed of bacteria, inflammatory cells and other substances. Shortly before infected mice die, the bacteria also begin showing up in the spleen and other organs, spreading there via the bloodstream.

Previous research had suggested that pneumonic plague might be spreading in the body in part through use of a protein known as plasminogen activator (PLA). The protein is a protease, which degrades other proteins. Goldman, Lathem and colleagues thought PLA might be a tool Yersinia uses to break open protective blood clots that form around pockets of infection. This clotting response is believed to be a way the body attempts to limit the spread of infections: Surround a pathogen with blood clots, and it can't reproduce and spread. Scientists speculated that breaking open the clots might be how Yersinia opened a path from the lungs into the blood.

When scientists infected mice with Yersinia that lacked PLA, though, they found infection ebbing in the lungs but spreading to the spleen. The mice still died, but it took them several days longer to do so. They concluded that the aggressive pneumonia and rapid death of pneumonic plague appears to depend on the activity of PLA.

"Pharmaceutical companies have large libraries of protease inhibitors, so hopefully someone will start the search soon for an inhibitor of PLA that is specific and non-toxic enough to be used as an adjunct treatment," Goldman says. "That might give us enough time to use antibiotics to save patients afflicted with pneumonic plague." Goldman hopes to conduct follow-up studies to learn more about how plague exploits PLA.

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Lathem WW, Price PA, Miller VL, Goldman WE. A plasminogen-activating protease specifically controls the development of primary pneumonic plague. Science, January 26, 2007.

Funding from the Midwest Regional Center for Excellence in Biodefense and Emerging Infectious Diseases Research supported this research.

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Contact: Michael C. Purdy
Washington University School of Medicine