Tuberculosis (TB) : Understanding the Disease, Part 2

by National Institute of Health

(Page 7 of 13)

Animal Models

In the early 1990s, Dr. Orme and his colleagues made an important contribution to speeding TB research when they developed a low-dose aerosol animal model of the disease. Their technique exposes mice to small amounts of M. tb delivered in a mist, thus mimicking the usual route to infection.

Dr. Orme uses the low-dose aerosol technique to probe basic questions of how immune system cells in the lung react to M. tb during the microbe's initial invasion. The model is playing an important role in applied research on new anti-TB drugs and vaccines too. Using this infection method on knock-out mice (genetically engineered to lack specific genes), Dr. Orme can determine the response an animal is having to a drug candidate in only five days, instead of the previously needed 30 days. He and other research teams can now screen significantly more compounds for possible activity against TB.

Dr. Orme and his colleagues also investigate the behavior of M. tb in test-tube experiments. Here, their primary interest is in studying M. tb growth when the organism is deprived of oxygen. This may mimic the situation in the lungs of people who have chronic or latent, rather than active, TB. At the moment, there is no good animal model of latent tuberculosis, says Dr. Orme, although he and other research groups are attempting to develop one.

Vaccine Efforts

The expertise and technologies available at the BSL3 site have also spurred research on vaccines. In 1997, NIAID expanded CSU's contract to include a vaccine screening service. Now, researchers from around the world can send candidate vaccines to be tested-at no cost-in the facility. To date, more than 120 vaccine candidates have been assessed for their ability to prevent infection in small animals.

On the vaccine development front, Dr. Orme again expresses optimism. Researchers in his lab are working to identify M. tb proteins that elicit a response from the immune system. This follows on the hypothesis, now widely accepted, that proteins secreted by the bacterium after it takes up residence inside the macrophage are targets for immune system action. A better understanding of these bacterial proteins might lead to vaccines designed to produce more of the immune system substances capable of destroying M. tb.

According to Dr. Orme, one of the remaining stumbling blocks to even greater progress in tuberculosis research is attracting enough top caliber students into the field. That, too, is getting easier to overcome, thanks in part to facilities for encouraging collaboration, such as those supported by NIAID. Then, too, there is Dr. Orme's own commitment to the cause. He is motivated to keep going by the enormity of worldwide TB. "The global scenario-if we don't improve our ability to treat and prevent this disease-is terrifying," he says.

Of Mice and Monkeys: Animal Models of TB Could Speed TB Treatment

Researchers from The Johns Hopkins University's Center for Tuberculosis Research in Baltimore are tackling one of the toughest problems in TB research-how to shorten the course of drug treatment for the disease. Currently, a complicated regimen of multiple antibiotics must be taken daily for six months or more. The most widely used way to administer TB drug therapy, called directly observed therapy, short-course, or DOTS, is hard and expensive to implement. The cost of the drugs can exceed the cost of hiring qualified observers to carry out the program, for example.

Hopkins researchers Jacques Grosset, M.D., William Bishai M.D., Ph.D., and Richard Chaisson, M.D., focus much of their research on a drug called moxifloxacin, or MXF, which is used to fight other bacterial infections. In 2003, their team, including fellow Hopkins TB researcher Eric Nuermberger, M.D., found that adding MXF to two other anti-TB drugs cut two months off the time normally required to cure mice of experimentally induced TB. The dosage and timing of this mouse TB drug regimen is designed to closely imitate drug activity patterns in human drug regimens. This study provides a strong rationale for considering clinical trials in humans, according to Dr. Grosset.

At the University of Pittsburgh School of Medicine, JoAnne Flynn, Ph.D., and her colleagues are developing a model of TB in non-human primates. Using the cynomolgus macaque, the researchers have created a model of TB that closely mimics both the active and latent stages of TB infection in humans. A non-human primate model of TB enables researchers to access lung tissue samples during latent and active disease, something that is not generally available from human patients, notes Dr. Flynn. Non-human primate models also would aid vaccine designers by providing information about the protective immune responses that fight off TB infection. Finally, this model would allow the study of drugs that might work against latent infection.

The University of Pittsburgh researchers used cynomolgus macaques to study a key process in TB infection, the formation and maintenance of granulomas. Tubercular granulomas are nodules containing M. tb -infected immune cells called macrophages. The granulomas keep M. tb from spreading by "walling-off" the infected area from the rest of the lung. A host of signaling molecules called chemokines and cytokines are likely employed by the immune system to help form and maintain granulomas, but their respective roles are not yet well understood.

Dr. Flynn and her colleagues, including Dr. Todd Reinhart, examined more than 300 granulomas that developed after the scientists infected monkeys with low doses of M. tb . Granuloma formation in macaques closely mimics that seen in humans. The study revealed that one class of chemokines was abundant in the gramulomas. The molecules likely serve to recruit specific kinds of immune cells to the areas where M. tb is present, the scientists reported. These findings provide new insight into the way immune system components and the TB bacterium may interact in the human lung.

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.