The ability of the tuberculosis microbe to outsmart a healthy immune system and cause disease has long puzzled medical scientists, but now researchers at the University of California, San Francisco have discovered one of the organism's most skillful means of protecting itself.

Study findings, reported in the new issue (October 1) of the Journal of Immunology, are especially significant for future development of new types of TB vaccines and possibly for more effective drugs.

The microbe, known as Mycobacterium tuberculosis, combines good survival technique with the right timing, said senior investigator Joel Ernst, MD, a UCSF professor of medicine, who specializes in infectious disease and also treats patients at San Francisco General Hospital Medical Center.

From their previous studies, the researchers knew that the organism lodges in the macrophage cells of the immune system, where infectious areas are sealed off in a kind of fibrous shell. The mission of the macrophages is to kill off foreign invaders, and they do so by taking their cues from an intricate chain of biochemical signals from other components of the immune system.

Working in the laboratory with human cells, the UCSF team analyzed this process of interactions at the cellular and molecular level. The researchers found that M. tuberculosis demonstrates its timing expertise by showing restraint, stepping in to disrupt the process only in the final phase. The microbe interrupts the activity of a protein called STAT1, which in turn blocks the ability of macrophages to respond to a crucial molecule of the immune system termed interferon gamma. Without the effective action of interferon gamma, the macrophages become inert and cannot kill M. tuberculosis.

The result is that M. tuberculosis survives despite development of a cellular immune response, Ernst explained.

"The study findings explain how the immune system of an otherwise healthy person is unable to destroy the
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Contact: Corinna Kaarlela
ckaarlela@pubaff.ucsf.edu
415-476-3804
University of California - San Francisco
4-Oct-1999