Discovery of new protein offers hope for new strategy in treating MDR-TB
Should efforts be aimed at boosting immune system?
Scientists at one of the world’s leading biotechnology laboratories have discovered a protein that may play a heretofore unexpected role in stopping the spread of tuberculosis. The finding could lead to a new type of therapy that would boost the immune system and sidestep the problem of drug-resistant strains of TB.
The association of the protein called osteopontin with TB infection was discovered after researchers at the Whitehead Institute for Biomedical Research in Cambridge (MA) and Massachusetts General Hospital in Boston surveyed an entire genome of a TB-infected mouse cell grown in the laboratory. It is the first time that a survey of an entire genome was used to identify genes turned on by infectious agents. This strategy could become a powerful new weapon in the war against other microbes, including HIV, they report in the June 10 issue of the Proceedings of the National Academy of Sciences.1
"These findings suggest that osteopontin is produced by the immune system to protect against TB and, therefore, may represent a new direction for therapy," says Richard Young, PhD, a research fellow at the institute.
Other immune system chemicals, most recently cytokines, have been successfully used as therapies in other diseases, including anemia and neutropenia, and have provided a new field for HIV treatment research.
Osteopontin’s apparent role in fighting TB infection came by surprise, says Gerald Nau, MD, PhD, a physician-scientist at Massachusetts General and lead author in the study. The study was designed to analyze differences in thousands of genes in cells infected with TB vs. those uninfected. Specifically, the technique identified the genes utilized by infected cells and found that certain types of RNA messengers or sentinels of the immune system called macrophages turned on the gene for osteopontin, resulting in increased production of the osteopontin protein.
"No one could have predicted this, and that is the beauty of the screening strategy we employed," he tells TB Monitor.
As the next step, the researchers looked at TB-infected cells in human tissue and found that, indeed, osteopontin was produced in lesions and, apparently, is responsible for calling other infection-fighting cells to surround the bacteria with masses of tissue called granulomas, which appear on lung X-rays as indicators of TB disease.
"In essence, by turning on osteopontin production, macrophages seem to help the immune system wall off the bacterium from the rest of the body," Nau says. "It is our own immune system’s response that leads to the granulomas that can be detected on patients’ chest X-rays."
A candidate for a new therapy?
The next question to be answered is, "What is the exact role of osteopontin?" Does it turn cells off or turn them on? Is it only protective against mycobacterium? Or does it help the body eradicate the organism by walling off the infection site? In follow-up studies on mice that lack the gene for osteopontin, preliminary results indicate that the protein does play a role in how the host handles infection. The big question is just how big a role big enough to become a candidate for therapy?
"We have some preliminary experiments that it probably does protect against TB, but that is still in the works, and we can’t give a definitive statement. Certainly, it is encouraging," au says.
So far, the researchers have found that osteopontin activates a response only against TB bacteria and not more common bacteria, such as Escherichia coli. However, they have found increased levels of osteopontin in silicosis, another disease in which granulomas result from breathing silica particles. Although it would take a large commitment of resources, Nau says it would be possible, once the human genome is mapped out, to see if there is genetic variation between those patients who would become actively infected with TB and those who live with the infection but never develop disease.
If osteopontin proves to play a major protective role against TB infection, it could lead to a completely different way of treating the disease augmenting the immune system rather than fighting the organism. That approach would eliminate the development of drug-resistant TB that results from poor compliance to drug regimens. A similar approach is being studied in HIV infection, in which patients are injected with a protein called interleukin-2 that boosts the immune system cells responsible for attacking the virus.
Developing a TB treatment that sidesteps resistance would be a major breakthrough, considering that the World Health Organization is predicting a new and deadly epidemic of drug-resistant TB. "Conditions have never been more perfect for a major global epidemic of drug-resistant TB," Young says. "Worldwide, we have increasing numbers of individuals with AIDS and of individuals with drug-resistant TB treated inappropriately with our best anti-TB drugs."
In related research, scientists at New York University Medical Center have been encouraged by the results of treating patients who have multidrug-resistant TB with aerosolized interferon (gamma).
For one month, the small study treated five patients who were smear- and culture-positive for TB. All the patients tolerated the drug, with only minor adverse effects, including muscle aches and cough. The patients gained weight or stopped losing weight and experienced a reduction in the size of their lesions.
The results, published in the Lancet, were encouraging enough that the study may be expanded.2
References
1. Nau G, Guilfoile P, Chupp G, et al. A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis. Proceedings of the National Academy of Sciences, June 10, 1997.
2. Condos R, Rom W, Schluger W, et al. Treatment of multidrug-resistant pulmonary tuberculosis with interferon-(Gamma) via aerosol. Lancet 1997; 349:1,513.
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