July 16, 2001 CLEVELAND -- Tuberculosis (TB) is one of the scourges of humans, infecting about one-third of the world's population, or two billion people. It kills an estimated eight million people annually. And while a vaccine exists for children, an effective vaccine for adults remains elusive.
A new study published in the July 15 issue of the "Journal of Immunology" may unlock a door in the search for a vaccine. The study from Case Western Reserve University's School of Medicine and University Hospitals of Cleveland details how the tuberculosis bacterium evades detection by the body's immune system.
An infectious disease, TB is caused by a bacterium called Mycobacterium tuberculosis, which can be transmitted through the air. Left untreated, TB can cause the development of cavities in the lungs and other tissues, leading to a variety of symptoms, including severe cough (at times with blood), fever, weight loss, and can become life-threatening.
Growth of the bacteria in the lungs of infected persons is controlled in many cases, but not eradicated, by the immune system. However, when immunity fails because of malnutrition, aging, or HIV infection, the bacteria grow, causing active TB of the lung. When an infection invades the body, the immune system is called upon to control and stop the infection. Important soldiers in the war against infection are scavenger cells called macrophages which chew up invading bacteria and deliver pieces of them to white blood cells named CD4 T cells.
Macrophages have a specialized set of molecules, called MHC-II (which stands for class II major histocompatibility complex). This set of molecules is used to present the pieces of invading bacteria to CD4 cells. These pieces, called antigens, are the way CD4 cells can recognize and eliminate invading bacteria.
The CWRU/UHC researchers have discovered that the TB bacterium stops the immune system from using this important piece of equipment from its arsenal. The bacterium inhibits the specialized MHC-II molecules by taking up residence in the macrophages and making a large protein in abundant quantities which interferes with MHC-II production.
Furthermore, the bacterium does this while engaging a macrophage receptor normally used for protection against a large number of infectious diseases. By employing that receptor and inhibiting MHC-II molecules, the bacterium evades detection.
"M. tuberculosis uses a critical receptor to prevent recognition by the human immune system, which allows it to survive in one of the most important cells of the immune system," said Henry Boom, professor of medicine and director of the Tuberculosis Research Unit at CWRU. "Better understanding of how the TB interferes with the immune system is necessary for developing vaccines against it," he added. "Targeting molecules of M. tuberculosis that interfere with the immune response may allow us to make an effective vaccine to prevent tuberculosis in adults," Boom said. "In order to stem the tide of tuberculosis in the world during the next 10 years, an effective vaccine is urgently needed."
While this study was conducted in mice, the researchers are currently testing their findings in human tissues. Boom shares senior author credit on the study with Clifford Harding, professor of pathology.
Sharing lead authorship are two students in the CWRU Medical Scientist Training Program, Erika Noss and Rish Pai. Other authors include Timothy Sellati and Justin Radolf from University of Connecticut Health Center; John Belisle from Colorado State University; and Douglas Golenbock from Boston Medical Center.
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