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Work in cells, animals, patients reveals toxin's role in asthma

SAN ANTONIO -- Five years ago, microbiologists at The University of Texas Health Science Center San Antonio discovered the toxin produced by a common respiratory bacterial pathogen, Mycoplasma pneumoniae. Joel Baseman, Ph.D., who led the discovery, said at the time that the toxin's presence in humans could be causing as many as 40 percent of all asthma cases.

Today there is a rising tide of evidence suggesting this is true. Dr. Baseman's colleagues in the School of Medicine at the Health Science Center are conducting clinical studies that indicate the CARDS toxin short for Community-Acquired Respiratory Distress Syndrome toxin is indeed initiating and intensifying asthma and other allergic airway diseases.

NIAID, Kleberg Foundation support

The National Institute of Allergy and Infectious Diseases (NIAID) this year awarded $11.5 million to fund further investigations led by Dr. Baseman, who directs the NIAID-sponsored San Antonio Asthma and Allergic Diseases Cooperative Research Center. "This award puts us in the top 10 centers in the country in the study of asthma and airway disease," Dr. Baseman said. "Obviously the NIAID thinks this work is novel, impactful and important."

The Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation also provides critical support to pursue innovative vaccine- and diagnostic-related research on the M. pneumoniae CARDS toxin and to translate these efforts into improved health in South Texas populations and worldwide. The National Trauma Institute sponsors aspects of these studies, as well.

Drug discovery and other investigations

The interdisciplinary research program, entirely conducted at the Health Science Center, involves microbiologists, immunologists, biochemists, adult practice physicians, pediatricians, pathologists and trauma surgeons. The faculty physicians provide care through UT Medicine San Antonio, the clinical practice of the School of Medicine.

One research group explores how the CARDS toxin interacts with the respiratory epithelium, the lining of the airway, leading to abnormal lung function. Others examine diagnostic aspects, drug discovery, and vaccine candidates that will alleviate asthma and other pulmonary conditions.

Once M. pneumoniae is in the lungs and airway, it stays there producing the CARDS toxin. "It's a persistent infection that causes inflammation, and we're just scratching the surface of how important this chronic infectious state is and how it could lead to long-term complications," Dr. Baseman said. "It may go well beyond asthma and allergy. If we are correct, this toxin is having a huge impact on acute and chronic lung disease globally."

Detection in children with asthma

Edward Brooks, M.D., a specialist in pediatric infectious diseases in the School of Medicine, is part of a team that enrolled 150 children divided into three groups: some with chronic, treatment-resistant asthma, some with acute symptoms requiring hospitalization, and some healthy controls. "One goal was to determine the frequency of M. pneumoniae infection in children with asthma," Dr. Brooks said. "Dr. Baseman's group has developed blood assays that are much more sensitive for detecting it. With the discovery of the CARDS toxin and the sensitive assays, we are able to much better detect whether a child has become infected with mycoplasma and whether it causes or worsens asthma symptoms."

The clinical core, led by Jay Peters, M.D., and other center collaborators, published a recent study on adult asthmatics in the journal Chest and will soon publish results on children. The researchers found chronic M. pneumoniae infections in all age groups, particularly in individuals with refractory asthma, the most difficult cases to manage. "Now it is hard to ignore that this is a bad toxin," Dr. Brooks said. "It is not just hanging out, doing nothing."

Of mice and crystals

Peter Dube, Ph.D., associate professor of microbiology and immunology, leads a separate group that is studying mouse models' responses to the CARDS toxin. "We are modeling different aspects of human disease and have a very relevant model that recapitulates what is seen in allergic asthma in humans," Dr. Dube said.

P. John Hart, Ph.D., professor of biochemistry, is experienced in X-ray crystallography, a technique to determine the three-dimensional structure of proteins. "The CARDS toxin from M. pneumoniae is an incredibly interesting molecular machine," he said. "The structure-based approaches coming from my laboratory, together with the cell-based, animal-based and patient-based approaches coming from laboratories of our collaborators, are working synergistically to provide an understanding of its mechanism of action and its role in airway disease."

Dr. Baseman summed it up: "This is five years later, and it's become even more of an intriguing and exciting story."

Contact: Will Sansom
University of Texas Health Science Center at San Antonio

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