The Immune Response to Tuberculosis
National Institute of Allergy and Infectious Diseases
“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.