Researchers Develop Better Tuberculosis Model
Researchers supported by the National Institute of Allergy and Infectious Diseases (NIAID) have demonstrated for the first time that chronic, slowly progressive tuberculosis (TB), the kind typically seen in humans, can be induced in monkeys. The finding, published in the April 1996 issue of the journal Nature Medicine, represents an important advance in the search for good animal models of TB.
"With an estimated 2 billion people--one-third of the world's population--infected with the TB bacterium, TB remains an urgent global health problem," says Anthony S. Fauci, M.D., director of NIAID. "Although most people with TB can be cured with a six to 12 month course of antibiotic therapy, the emergence of multidrug-resistant TB strains has created a pressing demand for new and better TB drugs, diagnostics and preventive measures, and has underscored the need for clinically relevant models in which to test them."
Prior to the current study, conducted by a team of researchers led by Marcus A. Horwitz, M.D., of the UCLA School of Medicine, rhesus monkeys provided the only established, albeit imperfect, nonhuman primate model of TB. Unlike humans, when rhesus monkeys are infected with even small amounts of TB bacteria, they invariably develop an acute, rapidly fatal form of the disease. Only about 10 percent of TB-infected humans, on the other hand, ever get sick, and the course of disease in humans is usually much more gradual than that seen in rhesus monkeys. The evaluation of new therapies for any disease ultimately requires animal models that develop a disease similar to that in humans.
Dr. Horwitz and his co-authors noted that cases of naturally acquired TB have been reported in cynomolgus monkeys, a type of macaque widely used in biomedical research. To find out whether this species could serve as an experimental model of the disease, the researchers inoculated groups of cynomolgus monkeys with decreasing amounts of TB bacteria. All of the monkeys became infected and most of them developed disease. However, unlike the rhesus monkey model, the severity of disease in the cynomolgus monkeys was highly dose-dependent. Animals receiving the largest doses of TB bacteria quickly became sick and died within a few weeks, while those receiving the smallest doses developed slowly progressive disease and survived for several months. Some animals in the low-dose groups even remained free of clinical symptoms throughout the study's seven and one-half month observation period.
"The pattern of susceptibility to infection and resistance to disease seen in the cynomolgus monkeys given the lowest doses of TB bacteria closely mimics the disease in humans," says Dr. Horwitz. He notes that this model provides an opportunity to study experimentally how TB bacteria survive in a dormant state within a primate host.
Dr. Horwitz and his colleagues will now try to determine just how long animals infected with very low doses of TB bacteria can remain symptom-free and whether such dormant infections can be reactivated by drugs that suppress the immune system, as frequently occurs in humans. Humans can stay healthy for many years before a dormant TB infection reactivates to cause disease. The researchers also will investigate how disease ultimately develops in monkeys who maintain long-term subclinical TB infections.
TB is the world's leading cause of death from a single infectious organism, killing more adults each year than AIDS, malaria and tropical diseases combined. In the United States, cases of TB increased more than 20 percent between 1985 and 1992. Although cases have declined in this country over the past few years, TB continues to be a significant health problem among people with AIDS, injection drug users and the homeless.
Dr. Horwitz's co-authors include Gerald P.Walsh, Ph.D., Esterlina V.Tan, M.D., Eduardo C. Dela Cruz, D.V.M., Rodolfo M. Abalos, M.D., Laarni G. Villahermosa, M.D., Leon J. Young, M.D., and Roland V. Cellona, M.D., D.P.H., of The Leonard Wood Memorial Research Center, Cebu, Philippines; and Jerome B. Nazareno, D.V.M., of the Simian Conservation and Breeding Corporation, Tanay, Philippines.
NIAID is a major supporter of research to find better ways to prevent, diagnose and treat TB. The Institute sponsors investigations into the development of TB vaccines and drugs, and studies of the molecular biology of the TB bacterium. A component of the National Institutes of Health, NIAID also conducts and supports research aimed at preventing, diagnosing and treating illnesses such as AIDS and other sexually transmitted diseases, asthma and allergies. NIH is an agency of the U.S. Public Health Service, part of the U.S. Department of Health and Human Services.
Reference:
Walsh GP, et al. The Philippine cynomolgus monkey (Macaca fasicularis) provides a new nonhuman primate model of tuberculosis that resembles human disease. Nature Medicine 1996;2:430-6.
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