Tuberculosis
Approximately 2 billion people, one-third of the world's population, are infected with the tuberculosis (TB) bacterium. This includes between 10 and 15 million people in the United States. 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. The National Institute of Allergy and Infectious Diseases (NIAID) is a major supporter of research to find better ways to prevent, diagnose and treat tuberculosis.
The World Health Organization (WHO) has designated Sunday, March 24, 1996 as World TB Day to draw attention to this dangerous epidemic.
Listed below are story ideas from NIAID-supported TB programs. To pursue these or other stories, please call the NIAID Office of Communications at (301) 402-1663. In this tipsheet:
- Building a Better TB Vaccine
- NIAID's TB Drug Screening Program
- Genetic Markers Link TB Cases and Offer Hope for Improved Diagnostics
- TB Gene Studies Lead to Promising New Drugs
A TB fact sheet, providing background information on the disease, is also included.
NIAID is one of 17 institutes of the National Institutes of Health (NIH), the federal focal point for biomedical research. NIH is an agency of the U.S. Public Health Service, Department of Health and Human Services.
TB Fact Sheet
TB Numbers
The WHO estimates that each year, more than 30 million people worldwide become newly infected with Mycobacterium tuberculosis, the TB bacterium--that's a new infection every second of the day. Nearly 9 million of these people develop active TB disease and more than 3 million people die from it each year. In the United States, TB deaths number about 2,000 annually. In 1993 the WHO declared TB a global public health emergency--the first, and thus far only, disease to receive such a designation.
The Difference Between TB Infection and Disease
As noted above, many more people are infected with TB than develop TB disease. Most people who become infected with the TB bacterium do not get sick--their immune systems isolate the bacteria in the cells lining the lungs' air sacs. Active TB disease often occurs in persons whose immune systems have been weakened by age, disease, improper nutrition or use of immunosuppressive drugs. Under these conditions, TB bacteria can break out of their dormant state and enter the bloodstream to cause disease. TB bacteria, and thus TB infection, can only be spread by persons with active disease. Coughing, sneezing or even talking by persons with active disease propels TB bacteria into the air, although it generally takes prolonged exposure to the bacteria before infection occurs. According to the WHO, a person with active TB will infect 10 to 15 other people over the course of a year. Without treatment, about half of those who develop active disease will die from it.
Re-Emergence of TB in the United States
A century ago, TB was a leading cause of death in the United States. Improvements in living conditions and the introduction of effective drug therapy contributed to a steady decline in the number of TB cases and deaths in the United States during most of this century. But between 1985 and 1992, cases of TB in the United States increased 20 percent, from 22,201 to 26,673. In crowded environments, such as large cities, TB's rise has been even more dramatic. For example, TB cases increased more than 100 percent in New York City between 1981 and 1991. Although adults between the ages of 25 and 44 have borne the brunt of the TB resurgence, increasing numbers of children also are being affected. Between 1985 and 1992 the number of cases of TB in children younger than 5 years of age increased by 36 percent. The number of cases in children ages 5 to 14 increased by 34 percent over the same period. An estimated 10 million persons in this country are infected with the TB bacterium and have the potential to develop active disease at some time in their lives.
The Problem of Drug-Resistant TB
The emergence of strains of tuberculosis resistant to standard TB antibiotics has contributed significantly to the increase in TB. Drug resistance results when patients do not take their medicine consistently for the six to 12 months that are necessary to complete a standard course of TB drug therapy. Early cessation of drug therapy allows the bacteria that had resisted the initial treatment to grow and develop further resistance. Strains of TB bacteria resistant to as many as six different TB drugs have been identified in the United States. A person with active TB that is drug resistant can then transmit drug-resistant TB to others.
TB and AIDS
The re-emergence of TB shares a close relationship with the AIDS epidemic. A large part of the increase in TB cases is due to the growing number of persons who are infected with both HIV, the AIDS virus, and the TB bacterium. The U.S. Centers for Disease Control and Prevention (CDC) estimate that 8.4 percent of worldwide cases of TB in 1995 can be attributed to HIV infection. This proportion will reach 13.8 percent by the year 2000. HIV infection increases the chance that dormant TB infection will become activated. The progression of TB disease also is accelerated in persons with HIV infection. In developing countries, especially in Africa, HIV infection is predicted to double or even triple the current rates of TB. This will further burden already strained TB control programs in these countries.
The BCG Vaccine
The only TB vaccine currently available, the bacillus Calmette-Guerin (BCG) vaccine, is given to infants in areas of the world where TB is most common as part of the immunization program recommended by the World Health Organization. Made from a live, but weakened cousin of the TB bacterium, BCG prevents the spread of TB infection within the body but does not prevent initial infection. The effectiveness of BCG in adults has varied widely in large-scale studies. In addition, persons immunized with BCG often have a positive reaction to the tuberculin skin test, thus diminishing the usefulness of this valuable diagnostic tool. Because of BCG's limitations, more effective vaccines are needed. NIAID-funded investigators recently have made promising advances toward developing alternatives and improvements to the BCG vaccine.
What is NIAID Doing About TB?
NIAID dramatically increased funding for TB research during recent years from approximately $3.5 million in 1991 to more than $30 million in 1995 to support a variety of investigations. The Institute's comprehensive research program encompasses studies of the epidemiology and natural history of TB, and basic and applied research to develop new ways to diagnose, treat and prevent TB. In late 1994, NIAID established a center at Case Western Reserve University in Cleveland, Ohio, to coordinate national and international basic and clinical research programs on TB. The center's primary goals are to develop new ways to measure the effectiveness of new drugs and to identify the immune responses that protect an individual from TB, information needed to evaluate candidate TB vaccines.
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TB Tip Sheet
Building a Better TB Vaccine
Mice immunized with a souped-up version of the BCG vaccine had much stronger immune responses to tuberculosis proteins compared with mice that were immunized with the standard BCG vaccine in studies led by NIAID grantee Richard Young, Ph.D. Dr. Young and his colleagues at the Whitehead Institute for Biomedical Research in Cambridge, Mass., used genetic engineering techniques to insert the genes for five different immune-stimulating compounds into the BCG organism. The compounds, known as cytokines, are chemical messengers that rally the immune system to launch a vigorous assault against invading organisms. The next step for the researchers will be to investigate whether the recombinant BCG vaccine can protect mice against infection with TB bacteria. Ref: P.J. Murray, et al. Proceedings of the National Academy of Sciences 1996;93(2):934-9.
Strains of mutant BCG developed by NIAID grantees Barry Bloom, Ph.D., and William R. Jacobs, Ph.D., at Yeshiva University in New York conferred equal or greater protection against TB infection in mice than did the standard BCG vaccine. Perhaps more importantly, the mutant strains, which require nutrients that mammalian hosts are unable to provide, were safe in immunodeficient mice. All immunodeficient mice that received the standard BCG vaccine died--those immunized with the mutant strains did not. This finding suggests that these BCG mutants might represent candidate vaccines that may be safe in HIV-infected patients and other immunocompromised individuals. The standard BCG vaccine can cause serious and even fatal disease in these patients. Ref: I. Guleria, et al. Nature Medicine 1996;2(3):334-7.
A new subunit vaccine--one made from protein components of the TB bacterium--induced protective immunity to TB in guinea pigs in a study by NIAID-supported scientists at the University of California, Los Angeles. Researchers led by Marcus Horwitz, M.D., immunized guinea pigs with the subunit vaccine and then sprayed TB bacteria into their lungs and into the lungs of a group of control animals that had not been immunized. At the end of the experiment, the immunized animals had only one-tenth the level of TB infection of the control animals. The research team currently is evaluating the subunit vaccine in primate models of TB. Ref: M.A. Horwitz, et al. Proceedings of the National Academy of Sciences 1995;92:1530-4.
Screening for New TB Drugs
A new NIAID-funded facility will acquire and screen natural and synthetic compounds in a search for new TB antibiotics. Located at the Southern Research Institute in Birmingham, Ala., and under the direction of NIAID grantee John Secrist, Ph.D., the facility will acquire approximately 6,000 compounds each year and coordinate their distribution to laboratory testing sites. A computerized chemical database will allow researchers to electronically search for compounds having chemical and physical characteristics similar to those that have shown anti-TB activity. Compounds that demonstrate activity against TB in vitro will advance to animal model testing. NIAID also supports a number of facilities for the preclinical evaluation of TB drugs in mouse models of the disease. Among these are the National Jewish Center for Immunology and Respiratory Medicine in Denver, and Colorado State University in Fort Collins, Colo.
Genetic Markers Link TB Cases and Offer Hope for Improved Diagnostics
Many of the molecular techniques that have revolutionized biomedical science over the past decade are just beginning to be applied to the study of TB. Important advances, however, already have been made.
NIAID-supported investigators have identified a number of tuberculosis gene mutations associated with resistance to a variety of standard TB drugs. These findings, combined with DNA fingerprinting techniques, recently led to an unsettling discovery about the spread of multidrug-resistant TB (MDR TB) in the United States.
NIAID grantee James M. Musser, M.D., Ph.D., of the Baylor College of Medicine in Houston, Tex., was part of a research team which found that a closely related family of drug-resistant TB bacteria had infected individuals at locations as widespread as New York, Florida, Georgia, Colorado and Nevada. All of the TB isolates from these locations had gene mutations associated with resistance to three standard TB drugs. DNA sequencing of the mutations indicated that the isolates recently had evolved from a single, common ancestor. The rapid spread of these strains of MDR TB could adversely impact TB control efforts in the United States. Ref: P. Bifani, et al. Journal of the American Medical Association 1996;275:452-7.
In ongoing studies, Dr. Musser and other NIAID-funded scientists are searching for additional genetic markers for TB drug resistance and exploring new technologies for rapidly analyzing TB DNA. New assays may allow physicians to detect and identify TB bacteria in samples of patients' sputum within 24 hours. Currently, the bacteria must be grown in petri dishes for two to four weeks before physicians can confidently diagnose TB disease. Ref: J.M. Musser, et al. Journal of Infectious Diseases 1996;173:196-202.
TB Gene Studies Lead to Promising New Drugs
Nearly two decades have passed since the introduction of a new drug for the treatment of TB. Increasing knowledge about the molecular biology of the TB bacterium promises to end this long dry spell.
NIAID-funded investigators have shown that a mutation in the TB gene known as inhA confers resistance to isoniazid, one of the most commonly used TB drugs. Further analyses of inhA by NIAID grantees William R. Jacobs, Ph.D., James Sacchettini, Ph.D., and John Blanchard, Ph.D., at Yeshiva University in New York have revealed that the protein encoded by the inhA gene plays a crucial role in building the TB bacterium's cell wall--information that the researchers have used to design a new class of TB antibiotics. Dr. Jacobs and his colleagues are developing "knock-out acids," drugs that interfere with the inhA protein's role in cell wall synthesis. In early laboratory experiments, these compounds have been equally active against both isoniazid-resistant and isoniazid-sensitive strains of TB. Ref: A. Dessen, et al. Science 1995;267:1638-41.
Investigations of the molecular biology of the immune response to Mycobacterium avium, a close relative of TB, has led to another potential new therapy for TB. Researchers led by Steven Holland, M.D., in NIAID's Laboratory of Host Defenses discovered that treatment with interferon gamma could boost the immune responses of patients infected with M. avium. In an ongoing clinical trial, many of the patients who have received this treatment have improved. These findings have led to a clinical trial of interferon gamma for treating patients with MDR TB. NIAID researchers are enrolling patients in this study, which has shown promising early results.
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