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Checkmate!

Checkmate!
Aggressive Strategies Move Toward Disarming Disease

February 2004

by Will Sansom

Micro-invaders make moves on our walls of immunity like the opposing pieces in a game of chess. We call the invaders "bugs," but scientists classify them as bacteria, parasites, fungi and viruses. Brilliant strategists, they will stop at nothing to outflank our defenses. Do we have what it takes to resist?

This flu season was difficult for a lot of people, especially the young. Scores of children died nationwide, including in Texas, and the high number of overall cases prompted the U.S. Centers for Disease Control and Prevention to declare a flu epidemic in December. Vaccine supplies dwindled as people lined up for inoculations. It was an unusually early outbreak of the flu, complicated by the fact that the vaccine protected against only some strains.

During flu season and throughout life, our bodies engage in a biological chess match with microorganisms. Gains and losses are measured in terms of "virulence." "Virulence is the capability of an organism to cause disease, usually in a population that is susceptible," said Joel B. Baseman, Ph.D., professor and chairman of the Health Science Centerís department of microbiology and immunology. "Virulence involves a whole spectrum of factors that determines the outcome of the battle between an infectious agent, such as the flu virus, and the host defenses."

As we line up for our flu shots each year, we probably think the shot will weaken the flu bug. But the truth is we are bolstering our immune systems to more effectively contend with the same strength of bug. "In this case we are not changing the virulence of the agent, we are changing us," Dr. Baseman said.

Virulence pits the attributes of microorganisms against the attributes of our own immune systems. A bug is more virulent if it is easily transmitted, survives a long time on surfaces or is able to colonize the body quickly. It is more virulent if it is resistant to antimicrobial drugs, evades the bodyís defense systems and has the ability to reproduce. "We know there are bugs and there are super-bugs," Dr. Baseman said. "The super-bugs have multiple ways in which they can invade cells and cause disease. These are the armaments of virulence."

Several scientists in the department of microbiology and immunology study the virulence of the super-bugs. For example, Assistant Professor Yan Xiang, Ph.D., is working with the vaccinia virus, from which the smallpox vaccine is made. The vaccine is safe and effective when administered to healthy individuals but causes rare and life-threatening complications in some people with immune deficiencies. Why? "The virus has more than 200 genes and uses some of them to evade the immune system," Dr. Xiang said. His goal is to decrease the virulence of the smallpox vaccine by removing the genes that disable cytokines, communication molecules that alert the immune system to an infection. The altered vaccine should cause a more-effective immune response to smallpox without side effects. A safer vaccine is of keen interest in this age of heightened homeland defense, because a large-scale terrorist attack could expose thousands of U.S. residents to the smallpox virus.

Assistant Professor Peter Dube, Ph.D., studies Yersinia pestis, the bacterium that causes plague. Not common in the United States, plague is a serious problem in Madagascar and India. Several drug-resistant species have emerged. Plague is transmitted by the fleas of rodents. "One of the biggest fears is that it can be a contagious disease," Dr. Dube said. "The pneumonic form invades the lung and spreads by coughing and sneezing. Ninety-five percent of persons who get it die. Usually by the time a person shows signs of disease, it is too late to treat."

Yersinia pestis is a subspecies of Yersinia pseudotuberculosis, which infects the gastrointestinal tract through food. Dr. Dube seeks to shed light on plague by examining this less-virulent cousin. "We found that in order to cause disease, these bacteria actually need to induce inflammation. They are capable of growing in tissue where a lot of tissue destruction has occurred. They thrive in hostile environments." Dr. Dube is examining this and other virulence factors with the goal of developing a plague vaccine.

Another colleague studies one of the major public health issues of our country. Associate Professor Guangming Zhong, M.D., Ph.D., is working with Chlamydia trachomatis, the agent that causes one of the nationís most common sexually transmitted diseases. An estimated 4 million new infections are reported annually in the United States, with a health care cost of $2 billion. "This bacterium has to grow inside cells of our body and it is the long-term intracellular growth that allows it to cause disease," Dr. Zhong said. "One of our research aims is to address how it survives in our bodyís cells for long periods of time without being detected by our bodyís defense systems. We have identified a virulence factor called CPAF that shuts down the host defense warning system. Efforts are under way to develop strategies for blocking CPAF function so that vaccine-induced immunity can effectively detect and attack this infection and prevent associated health problems."

In each laboratory, the scientists investigate virulence and seek to develop or improve vaccines. What they learn could shift the balance of power in the chess match of our health.



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