Researchers Discover How Tuberculosis Bacteria Invade Cells

Understanding how the bacterium invades cells may be an important first step toward developing a vaccine to prevent tuberculosis, says Jeffrey S. Schorey, Ph.D., an instructor of medicine and lead author of a paper in the August 22, 1997, issue of Science. Although such a vaccine could be developed only after many more years of study, researchers are excited about the new insight into the common and deadly microbe.

"This study helps us understand what's special about this bacterium and what makes it such an effective pathogen," says Eric J. Brown, M.D., co-author of the paper. Brown is a professor of medicine and of cell biology and physiology at the School of Medicine.

Tuberculosis is a growing global menace that kills more people than any other infectious disease. Three million people die from it each year, and as many as one-third of the world's population is infected with Mycobacterium tuberculosis, the bacterium that causes the disease.

Researchers have long known that M. tuberculosis makes its living by preying on macrophages, the immune system warriors that usually consume bacteria. The bacterium enters a macrophage and apparently multiplies until the cell ruptures, releasing more bacteria to attack other macrophages.

Schorey, Brown and colleagues conducted test-tube studies with M. tuberculosis and a few of its close relatives including M. leprae, which causes leprosy, and M. avium, which frequently infects AIDS patients. The researchers found that all three bacteria share a special trick for finding and invading cells. They grab a protein discarded by the immune system and use it to lure the macrophages to their death.

Normally, when a bacterium enters the body, the immune system responds by tagging the bug with certain proteins that alert the macrophages. Any macrophage (literally "big eater") that detects the proteins will attach itself to the intruder and try to consume it.

Tagging a bug requires a highly choreographed interaction of many proteins, including one called C2a. When combined with another protein, C2a forms a potent enzyme that plays a major role in labeling intruders. After the job is done, C2a breaks off from its partner and floats in the blood with no known function.

Humans may have no use for discarded C2a, but it's apparently invaluable for the disease-causing mycobacteria. Schorey's experiments demonstrated that the bacteria grab onto the protein and use it to create a new label that helps bacteria adhere to the macrophage. The protein also seems to work like a pass key that gives the bacteria easy entrance to the cells. The researchers found that adding infinitesimal amounts of the protein to test tubes containing bacteria and macrophages greatly increased the number of infected cells.

Previous studies have described other invasion techniques used by mycobacteria, but the C2a strategy stands out for one major reason: It's used only by the types of mycobacteria that cause disease. "This is why we think C2a is important for the virulence of these bacteria," Schorey says.

The next important step is to find the bacterial molecule that interacts with C2a, Schorey says. He and his colleagues also plan to move beyond test-tube studies to observe mycobacteria in immune-compromised mice.

If researchers can find the molecule that binds to C2a, and if the results of animal studies echo the findings from the test-tube studies, this new invasion mechanism could form the basis for developing a novel vaccine, Schorey says.

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This research was supported by the National Institutes of Health.