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Cracking a Microbiology Cold Case

Health Science Center researchers put the freeze on a respiratory toxin after 50 years

August 2006

by Will Sansom

The mycoplasmas are the smallest of all bacteria, almost inscrutable in their ways of operating. Microbe hunters seek the answers to many questions about them. What are mycoplasmas doing to our bodies? How do they persist in our tissues? Can we develop vaccines against them?

For more than three decades, Joel B. Baseman, Ph.D., professor and chair of the department of microbiology and immunology at the Health Science Center, has looked at countless microscope slides and bacterial cultures to answer the questions.

This spring, Dr. Baseman, senior author, and his protégé, T.R. Kannan, Ph.D., lead author, reported what Dr. Baseman says is the most exciting discovery ever to come out of his laboratory: identification of the first toxin produced by a disease-causing mycoplasma. "This discovery is arguably the most important in the field since the discovery of the classical toxins of diphtheria and pertussis decades ago," Dr. Baseman said.

The toxin is produced by the respiratory pathogen Mycoplasma pneumoniae. "This mycoplasma species is incredibly common, and is spread by sneezing, coughing, talking and touching hands to nose," said Dr. Kannan, instructor of microbiology and immunology.

Half of all people are infected with it. By persisting in the lungs and flaring up from time to time, it is thought to be responsible for millions of cases of child and adult asthma. "Even cases of the sniffles that we call colds may actually be manifestations of infection with this bacterium," Dr. Kannan said. "Studies of its mechanisms of operation could improve diagnosis and treatment of a wide range of human diseases, including acute and chronic airway diseases, but also diseases affecting other parts of the body, such as the heart, central nervous system, skin, joints, kidney and liver, that appear to be targets of M. pneumoniae and its toxin, as well."

The historic paper was published in Proceedings of the National Academy of Sciences, and was so well received by the world’s scientists that it was included in the Research Highlights section of Nature. Harvard Medical School’s R. John Collier, Ph.D., one of the leading toxin experts in the world, highlighted the paper as a must read for the "Faculty of 1000 Biology," composed of elite scientists around the world. The Faculty of 1000 Biology Web site (www.f1000biology.com/browse/) invites members to rate journal articles for listing on the site, with the purpose of directing scientists to the most significant papers being published.

M. pneumoniae accomplishes its ill effects by escaping drug therapy, by having the unique ability to persist in its host for long periods, and by producing the newly discovered toxin, the researchers said. "It can go deep inside cells to escape therapy, becoming quiet and dormant to escape detection," Dr. Kannan said. "This bacterium is so small that it cannot live outside the host, so it persists in order to maintain its relationship with the host."

It is the first microbial toxin found to date that disrupts human cells in two ways rather than one, Dr. Baseman said. One way is described in the railroad analogy on these pages. The second way the toxin creates chaos is by breaching and disrupting cell membranes.

Dr. Baseman has just received a multimillion-dollar grant to study the toxin’s relationship to diseases, particularly asthma. This grant funds collaborative studies with basic and clinical scientists in the departments of microbiology and immunology, medicine and pathology at the Health Science Center and the department of medicine at the U.T. Southwestern Medical Center at Dallas. A key future goal is to establish an airway center at the Health Science Center that is equivalent to some of the other well-established research entities within the university. Those established centers include the Research Imaging Center and the Sam and Ann Barshop Institute for Longevity and Aging Studies,to name just a couple. The discovery of this new toxin is that important, the researchers said.

"M. pneumoniae is involved in disease paths throughout the body," Dr. Baseman said. "We have looked for a toxin that can explain it all. Now we’ve got it. We have uncovered a 50-year-old mystery in bacterial pathogenesis."

Tampering Toxin
A train derailment (pictured above) can help illustrate how a tiny bacterium wreaks major havoc

1. A railroad switch, which guides the train from one line of tracks to another, is controlled electrically by a signal box.

2. A bacterium bug tampers with the signal box and corrupts the switch mechanism.

3. The train receives incorrect signals, heads off the tracks and derails.

The bacterium bug is the mycoplasma pneumoniae toxin discovered by Drs. Joel Baseman and T.R. Kannan. The act of tampering, or resetting the switch box, is called, in scientific terms, ADP ribosylation. The toxin snips a piece of DNA from a target protein, usually a protein residing in the lungs where m. pneumoniae, a respiratory disease agent, first infiltrates. That tampering results in the protein becoming dysfunctional, sending incorrect signals to itself and affecting other proteins. The process, or derailment, continues from the lungs to other spots throughout the body.


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