Tuberculosis (TB) : Understanding the Disease

by National Institute of Health

(Page 6 of 13)

The Immune Response to TB

"In my research," says Gilla Kaplan, Ph.D., of the Public Health Research Institute in Newark, New Jersey,

"I ask what aspect of the immune response to infection protects some people from developing TB, and what is missing in those people who develop the disease."

Both human and bacterial factors contribute to the eventual outcome of Mycobacterium tuberculosis (M. tb) infection. If scientists could identify how these host and pathogen factors interact, there might be ways to, for example, boost immune responses or draw the TB bacteria out of latency and make them more vulnerable to drug attack.

One response under study by Dr. Kaplan is inflammation caused when a chemical called TNF- α is released from certain immune system cells exposed to M. tb. Some inflammation is good because it helps the body eliminate the disease-causing organisms; but uncontrolled inflammation can cause just as much damage as the disease itself. Dr. Kaplan and her colleagues are studying whether the drug thalidomide and its analogues can dampen excess inflammation caused by TNF-α. Although the approach has not yet been tested in humans, it has shown promise in animal models of TB.

Dr. Kaplan's lab also looks at the problem from the bacterium's viewpoint. Human immune system weapons deployed early-just after the bacterium invades the lung-differ from those used by the immune system during latent infection, Dr. Kaplan explains. To survive in humans, TB bugs must switch on different genes in response to the changing immune response. In effect, the bacteria's changing genetic profile mirrors the human immune responses, Dr. Kaplan says.

She and her collaborators, including Dr. McKinney of Rockefeller University, sought a better understanding of this molecular mirror by analyzing lung tissue samples taken from two groups of TB patients. The first group had active TB; the second group of patients was infected, but did not have any TB symptoms. Dr. Kaplan's team is pinpointing which human immune response genes are expressed in these various states, while researchers in Dr. McKinney's lab are determining which bacterial genes are switched on at each phase. The scientists will use what they learn from these experiments to improve a rabbit model of TB, which should better mimic latent TB infection in humans.

Late in 2004, Dr. Kaplan collaborated with NIAID researchers in NIAID's Division of Intramural Research, led by Clifton E. Barry, III, Ph.D., to discover how a particularly virulent strain of M. tb causes severe disease. Evidence from TB clinics suggested that families of strains of M. tb called W-Beijing are more likely to cause severe disease and to be multi-drug resistant than other strains. In mice, members of the Strain W-Beijing are deadly. Drs. Kaplan and Barry found a molecule produced by W-Beijing strains that seems to prevent immune system cells from releasing several infection-fighting chemicals. This molecule, PGL, is not produced by many TB strains.

When the NIAID scientists altered the TB bacteria to remove their ability to produce PGL, the bacteria were not as lethal to mice, although the organisms could still reproduce inside the lung. The research that found a link between PGL production and "hyper-lethality" of certain TB strains was conducted in mice, so any role that PGL may have in human TB must still be determined, notes Dr. Kaplan. She and colleagues in Cape Town, South Africa, and Dr. Barry and colleagues in Masan, South Korea, are now beginning the human studies needed to see if PGL-producing strains cause more severe disease or are more likely to be resistant to TB drugs than TB strains that do not make PGL.

TB Research Attains New Heights in Colorado

"This is a jolly interesting time in tuberculosis research," says Ian Orme, Ph.D., of Colorado State University (CSU). Dr. Orme has not always been as optimistic as he is today and, considering how difficult research on tuberculosis can be, it is easy to understand why; the microbe that causes tuberculosis demands careful handling if it is to perform at all.

Roadblocks in Research

Mycobacterium tuberculosis (M. tb) is surprisingly difficult to grow under laboratory conditions and, when it does, lab personnel must be protected from accidental infection. Work on virulent strains of M. tb must take place in sophisticated biosafety level three (BSL3) laboratories, of which there a limited number in the United States.

TB research has also been hindered because scientists lacked animal models that could faithfully mimic the disease. For years, investigators studied TB in mice and guinea pigs by injecting the bacterium directly into the animals' bloodstream. Although researchers could learn some things about late-stage tuberculosis with these animal models, the early and more typical pulmonary form of the disease could not be easily studied.

Until recently there was no rapid, accurate way to screen potential drug candidates for their anti-TB properties, creating still another roadblock. Add to this the limited interest large pharmaceutical companies have shown in bringing new anti-TB drugs to market and it's not surprising that veteran TB researchers became disheartened.

Happily, much has changed. Dr. Orme credits NIAID's support for a TB research materials, vaccine, and drug testing facility at CSU with hastening that change. The facility at CSU includes a state-of-the-art BSL3 laboratory where virulent strains of M. tb can be grown, stored and distributed upon request to researchers throughout the country.

About the Author

NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research.