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 bacteria that cause tuberculosis. Now that we know this, the development of vaccines and the immunotherapy of tuberculosis can be approached more rationally," he said.
The UCSF study is a prime example of how basic science research is applied to the study of disease, Ernst added. Studies done elsewhere determined the cellular and signaling pathways initiated by interferon gamma, providing the UCSF team with the tools to carry research one step further. "With this information, we traced the pathway every step of the way, identifying the impact of M. tuberculosis," he said.
UCSF pulmonary specialist Philip Hopewell, MD, who also is associate dean of the UCSF School of Medicine at SFGHMC, has been active in TB research and control for 25 years. Reviewing the study results he said, "The only way that the global tuberculosis epidemic will be controlled is through the use of an effective vaccine. These findings bring us closer to understanding the immune response to infection with the tubercle bacillus and, thus, provide important information upon which vaccine development will depend."
In a person, the TB microbe causes a chronic bacterial infection that usually affects the lungs but also attacks other organs. It is spread through the air when a person with active TB disease of the lungs or larynx coughs, sneezes, or shouts. It is most prevalent in densely populated areas and the inner-city where people often live in close quarters.
Worldwide, an estimated 1.5 billion persons are infected with TB and about 3 million die each year from the disease, so implications for controlling infection are enormous, Ernst emphasized. Areas with the highest rates of TB infection include Sub-Saharan Africa, India, China, and the Philippines. An estimated 15 million Americans are infected, although only about 10 percent of those infected ever develop the disease. An estimated 10-12 percent of the San Francisco population is infected.
Factors contributing to TB infection rates in the U.S. include the HIV/AIDS epidemic, because persons with HIV are particularly vulnerable to infection; increased numbers of immigrants from countries with a high incidence of TB and crowded housing; and an increased population of homeless and injection drug users.
Study co-investigators were Li-Min Ting, PhD, post-doctoral scholar; Anne C. Kim, UCSF second-year medical student; and Ashok Cattamanchi, now a medical student in Chicago, all of the UCSF Rosalind Russell Arthritis Research Laboratory and the Loewenstein Laboratory for Mycobacterial Research at SFGHMC. The research was supported by grants from the National Institutes of Health, the University of California AIDS Research Program, and Berlex Biosciences, Richmond, Calif.
Journal
The Journal of Immunology