Researchers Discover Attack Route Used By Plague Bacterium's Killer Toxins

"This finding raises the intriguing possibility that YopM may contribute to the development of disease by altering human gene expression," said Susan Straley, Ph.D., professor of microbiology and immunology, UK College of Medicine, and director of the research team for the project. "We believe that further study of the mode of action of this protein in host cells will provide insight into bacterial causes of disease and cell biology."

Yersinia invades an organism and attaches itself to cell surfaces. YopM is one of six toxins called Yops that Yersinia injects directly into the cell. Yops act by scrambling the functions necessary for humans to mount a defense against the bacteria.

Little is known about how these mysterious toxins function to destroy the immune response, but researchers believe Yops target phagocytic cells, the body’s first line of defense against invaders. The bacterial killing response of the phagocytic cells is paralyzed, and the cells are rendered incapable of sending messages to other cells to begin an immune response to the pathogen.

UK researchers propose that YopM uses complex interactions to reach and pass through the controlled gates of the nucleus. They believe YopM binds to the exterior of acidic compartments, called endosomal vesicles, and moves as new vesicles arise. YopM may act to prevent enter the nucleus by itself or it may become associated with a protein. Once the nucleus is invaded, YopM may act to prevent the development of a defense that is needed for clearance of bacteria from the body.

"We are aiming future studies at identifying YopM’s ultimate molecular target and hope to reveal the molecular partners used by the protein on its journey through the human cell," Straley said. "These studies will

provide a new window into how our cells function, and the understanding gained from them will benefit all endeavors that depend upon understanding how the human body works."

The researchers’ work helps biotechnology companies develop improved therapies for many diseases, Straley said. Scientists view Yersinia pestis as a useful model pathogen that merits the type of study underway in Straley’s lab because several broadly applicable principles have been discovered from such studies in the past.

Moreover, plague still poses a public health threat and continues to be a global problem. If a drug-resistant strain should emerge abroad, Americans are only a plane ride away from potential exposure to it. In the United States, 41 cases were reported between 1993 and 1996. Worldwide, there are 1,000 to 2,000 cases each year, and there is always the concern that a serious epidemic may develop.

First author on the paper is researcher Elzbieta Skrzypek, Ph.D., scientist II, UK College of Medicine, and Clarissa Cowan, research analysts, UK College of Medicine, also contributed to the work. The project was supported until September 1997 by the Department of the Army and since then by the National Institute of Allergy and Infectious Diseases.