The ability of the tuberculosis microbe to outsmart a healthy immune system andcause disease has long puzzled medical scientists, but now researchers at theUniversity of California, San Francisco have discovered one of the organism'smost skillful means of protecting itself.
Study findings, reported in the new issue (October 1) of the Journal ofImmunology, are especially significant for future development of new types ofTB vaccines and possibly for more effective drugs.
The microbe, known as Mycobacterium tuberculosis, combines good survivaltechnique with the right timing, said senior investigator Joel Ernst, MD, aUCSF professor of medicine, who specializes in infectious disease and alsotreats patients at San Francisco General Hospital Medical Center .
From their previous studies, the researchers knew that the organism lodges inthe macrophage cells of the immune system, where infectious areas are sealedoff in a kind of fibrous shell. The mission of the macrophages is to kill offforeign invaders, and they do so by taking their cues from an intricate chainof biochemical signals from other components of the immune system.
Working in the laboratory with human cells, the UCSF team analyzed this processof interactions at the cellular and molecular level. The researchers found thatM. tuberculosis demonstrates its timing expertise by showing restraint,stepping in to disrupt the process only in the final phase. The microbeinterrupts the activity of a protein called STAT1, which in turn blocks theability of macrophages to respond to a crucial molecule of the immune systemtermed 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 cellularimmune response, Ernst explained.
"The study findings explain how the immune system of an otherwise healthyperson is unable to destroy the bacteria that cause tuberculosis. Now that weknow this, the development of vaccines and the immunotherapy of tuberculosiscan be approached more rationally," he said.
The UCSF study is a prime example of how basic science research is applied tothe study of disease, Ernst added. Studies done elsewhere determined thecellular and signaling pathways initiated by interferon gamma, providing theUCSF team with the tools to carry research one step further. "With thisinformation, we traced the pathway every step of the way, identifying theimpact of M. tuberculosis," he said.
UCSF pulmonary specialist Philip Hopewell, MD, who also is associate dean ofthe UCSF School of Medicine at SFGHMC, has been active in TB research andcontrol for 25 years. Reviewing the study results he said, "The only way thatthe global tuberculosis epidemic will be controlled is through the use of aneffective vaccine. These findings bring us closer to understanding the immuneresponse to infection with the tubercle bacillus and, thus, provide importantinformation upon which vaccine development will depend."
In a person, the TB microbe causes a chronic bacterial infection that usuallyaffects the lungs but also attacks other organs. It is spread through the airwhen a person with active TB disease of the lungs or larynx coughs, sneezes, orshouts. It is most prevalent in densely populated areas and the inner-citywhere people often live in close quarters.
Worldwide, an estimated 1.5 billion persons are infected with TB and about 3million die each year from the disease, so implications for controllinginfection are enormous, Ernst emphasized. Areas with the highest rates of TBinfection include Sub-Saharan Africa, India, China, and the Philippines.
An estimated 15 million Americans are infected, although only about 10 percentof those infected ever develop the disease. An estimated 10-12 percent of theSan Francisco population is infected.
Factors contributing to TB infection rates in the U.S. include the HIV/AIDSepidemic, because persons with HIV are particularly vulnerable to infection;increased numbers of immigrants from countries with a high incidence of TB andcrowded housing; and an increased population of homeless and injection drugusers.
Study co-investigators were Li-Min Ting, PhD, post-doctoral scholar; Anne C.Kim, UCSF second-year medical student; and Ashok Cattamanchi, now a medicalstudent in Chicago, all of the UCSF Rosalind Russell Arthritis ResearchLaboratory 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.
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