UTHCT scientist identifies genetic mutation that increases a person’s odds of developing active tuberculosis

Monday, December 19, 2005

Results from a study indicate that a small mutation in a particular gene increases a person’s odds of developing active tuberculosis, said Pedro Flores-Villanueva, MD, assistant professor of immunology at The University of Texas Health Science Center at Tyler.

“A large number of adults who develop tuberculosis carry this mutated gene,” Dr. Flores-Villanueva said. Thus, a successful therapy targeting this gene could prevent many people from developing TB. The results of his study are published in the Dec. 19 issue of The Journal of Experimental Medicine.

“We have identified one of the genes that may explain why some individuals are more susceptible to tuberculosis and why they cannot control the TB infection. This knowledge could be used to design new therapies and clinical interventions to prevent people from developing active TB,” said Dr. Flores-Villanueva, who has been at the Health Center for about nine months.

Worldwide, it is estimated that almost one billion people will become newly infected with TB, more than 150 million will become sick, and 36 million will die between now and 2020, unless the spread of TB is better controlled. Each year there are more than 8.8 million cases and close to two million deaths attributed to tuberculosis; 100,000 of those two million deaths occur among children.

Dr. Flores-Villanueva“Our study focuses on identifying why people develop TB. Only 10 percent of the people who are infected with the TB bacteria go on to develop the disease,” Dr. Flores-Villanueva said. “We want to know about the immune system of these individuals and what makes them more susceptible to TB.”

Genes create proteins, which are crucial to pathways, or operations, inside the cell. Once you identify what pathways are affected by changes in these proteins, you can develop new therapies, he said.

Tuberculosis is a chronic bacterial infection that usually targets the lungs, though other organs sometimes are involved. Most people infected with TB do not have symptoms of the disease; they have a latent tuberculosis infection. Tuberculosis symptoms include a low-grade fever, night sweats, fatigue, weight loss, and a persistent cough.

Many people with latent TB develop active tuberculosis each year. Once the disease becomes active, it can spread to other people. The person with TB coughs or sneezes and the airborne TB bacteria are inhaled by another person who then may develop tuberculosis. TB is not easily spread from person to person. You must be in close contact with someone with active TB to contract the disease.

“These are slow-growing bacteria. The genetic factors are not the only factors controlling this disease,” he said. The complex interaction of several factors determines if someone develops active TB, Dr. Flores-Villanueva said. Besides genetic mutations, these other factors include the person’s nutrition, his health, his lifestyle, and how potent the particular TB strain is.

“This is complicated. Several genes might be controlling the expression of the genetic trait that makes a person more susceptible to tuberculosis,” Dr. Flores-Villanueva said. Dr. Adrian Hill, an English scientist, previously discovered a link between the mutation of another gene and susceptibility to TB. The genetic mutation identified by Dr. Hill is more common in Africans, while the one identified by Dr. Flores-Villanueva is found more frequently in Hispanics and Koreans.

“We’ve found that a protein called MCP-1 is important in marshaling the immune system’s response to a TB infection. If the amount of this protein is too high, it interferes with the immune system’s response to TB,” he said. MCP-1 attracts immune cells to new sites of infection, making MCP-1 an important part of the immune system’s early response to TB.

“The genetic mutation we found produces a significant increase in the amount of MCP-1. These excessive levels of MCP-1 keep your immune system from fighting off the TB infection,” Dr. Flores-Villanueva said. The high level of MCP-1 restricts the production of another crucial chemical, interleukin-12, a key factor in controlling infection, he said.

Though Dr. Flores-Villanueva and his team at UTHSCT have found one genetic link to tuberculosis, much remains to be understood.

“Some individuals who have this mutation do not develop tuberculosis. We want to know why. There is some evidence that the gene we found is working with another gene to make people more susceptible to TB,” he said.

Dr. Flores-Villanueva’s research was supported by funds from the National Institutes of Health. He has been working on this research for more than four years.

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