Controlling Tuberculosis Through Genetics

"Gezundheit!" is an adage you’ll never hear in Dr. Robert L. Hunter’s mouse lab.

Dr. Hunter, chair of The University of Texas Medical School at Houston’s department of pathology and laboratory medicine, is the principal investigator for a five-year $2 million National Institutes of Health study on tuberculosis, titled "Genetic Control of Pulmonary Cavities in Tuberculosis." Because mice don’t sneeze or cough – activities necessary to spread tuberculosis – they are utilized to investigate the disease process.

Collaborators on the grant include Drs. Chinnaswamy Jagannath, Jeffrey Actor, Audrey Wanger, and Lisa Armitige, all from the department of pathology and laboratory medicine at UT-Houston Medical School, and Dr. Peter Small, from the department of medicine at Stanford University.

Dr. Jagannath, working with Dr. Hunter as a co-investigator, also has two NIH- funded projects of his own, a five-year $1.25 million grant to study reactivation tuberculosis, and a $1.25 million award for "Characterization of a Mycobacterium Tuberculosis Vaccine." The latter, using animal models, will enable Dr. Jagannath to develop a better TB vaccine.

Tuberculosis bacteria have an unusual life history. While most animals can be infected experimentally, natural infection is confined to humans. Without transmission from person to person, tuberculosis would soon become extinct. Yet the disease survives in very small populations of people. Typically, people become infected by breathing airborne bacteria. These organisms grow transiently but become dormant as the person develops immunity.

The critical phase transpires 10 to 40 years later when bacteria reactivate in the lung to produce cavities. Tuberculosis grows to vast numbers in these cavities, even though a high level of immunity exists in all other parts of the body.

This transforms people into "bacterial atomizers" said Dr. Hunter. They spread infectious organisms every time they cough or sneeze. One person can infect hundreds in a short period of time. There is a delicate balance between the host and organism during this time. If the host is strong, the disease may heal spontaneously and the organisms revert to dormancy. If, however, the host is weakened by factors such malnutrition or stress, the disease progresses, producing the characteristic syndrome of TB, sometimes referred to as consumption.

Because transmission of the infection by people with cavities is so efficient, one-third of the world’s population carries TB, even though the disease has declined for a century. Crowding and malnutrition are important factors in the spread of infection. Afghan refugees over the last 20 years, for instance, have had a very high incidence of TB. Additionally, global travel, the rise of AIDS, and an aging population with diminishing immune systems have all contributed to the re-emergence of this disease.

Before the advent of antibiotics, TB was treated in a sanitarium. Rest, good nutrition, and fresh air were the best therapies available, and increased the likelihood of recovery.

Tuberculosis kills 2.5 to 3 million people annually – more than any other infection. Poverty, homelessness and immigration are becoming more common. These same conditions also caused a 19th-century epidemic. A vaccine for tuberculosis, bacille calmette guerin, is given at birth in many countries to prevent childhood TB and meningitis.

However, bacille calmette guerin is ineffective against adult pulmonary tuberculosis, the phase of the disease on which Dr. Hunter and his colleagues are working. Tuberculosis can be stopped or slowed by improvements in housing, adding fresh fruits and vegetables to the diet, and by overcoming zinc deficiency and protein malnutrition, in addition to adding the TB vaccine. These proactive measures have substantially contributed to the reduction of TB over the past 150 years.

Dr. Hunter’s goals include identifying the mycobacterium tuberculosis genes responsible for creating pulmonary cavities. The approach is based on the finding that strains that lose portions of their genome through deletion have reduced or abolished ability to produce cavities. He and his associates will build a matrix database that includes a whole genome DNA in order to ascertain which genes are responsible for producing toxic lipids and creating pulmonary cavities. They will then use conventional genetic approaches of gene knockouts and complementation.

The current public health directive designed to combat TB is directly observed therapy. With directly observed therapy, twice a week a nurse observes, as noncompliant TB patients take their pills.

"That’s the most effective knockout punch we have right now," Dr. Hunter said. "If we could find a way to block the formation of cavities, mycobacterium tuberculosis would soon become extinct."

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©2006 Texas Medical Center

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