July 9, 2002 NYU School of Medicine scientists have discovered a novel role for the toxin that is responsible for toxic shock syndrome, a deadly infection linked to the use of highly absorbent tampons. They report in a new study that the toxic shock toxin, produced by the notorious bacterium Staphylococcus aureus, acts as a sort of master switch that blocks the infecting bacterium's production of most of its other disease-causing proteins.
Staph causes a wide range of maladies, from local infections of the skin, lungs, bones and heart valves, to toxic shock syndrome and death, and it is a leading cause of hospital-acquired infections, striking some 500,000 patients each year. The bug can infect surgical wounds and has a great affinity for implanted foreign objects, such as catheters. It can also be completely benign – the bacterium regularly inhabits our nasal passages without causing disease.
What accounts for the organism's ability to cause such widely different effects in the body? The new study, published in this week's issue of the Proceedings of the National Academy of Sciences, advances the understanding of how this bacterium goes about its unsavory business, says Richard Novick, M.D., Professor of Microbiology and Medicine at NYU School of Medicine, who led the new study.
In the new study, Dr. Novick and co-workers Nikola Vojtov and Hope Ross, Ph.D., demonstrate toxic shock toxin inhibits the genes that encode most of the other toxic proteins produced by Staph. This finding explains why Staph strains causing toxic shock syndrome produce few of the other staphylococcal proteins involved in the causation of disease.
"Our study essentially adds a new dimension to the way we understand bacterial pathogenesis," says Dr. Novick. Understanding how this dangerous bug operates is an important field of research, especially because in recent years Staph increasingly has become resistant to the most commonly used antibiotics. The development of antibiotic-resistant strains of Staph and other bacteria has caused widespread alarm that one day there may be many so-called superbugs resistant to all known antibiotics. Dr. Novick's laboratory has long been involved in Staph research with an aim to developing novel therapies to combat the bug.
Staph is a particularly versatile pathogen. It ordinarily produces as many as 40 different proteins that are exported by the organism and interact with the tissues of the infected individual in a complex way to cause abscesses and other forms of infection. Some of these proteins are recognized by the cells and tissues of the infected individual, provoking an elaborate set of defensive reactions by the body.
At the same time, there is a subset of Staph infections caused by a single toxin - such as toxic shock syndrome - that are not associated with typical local inflammation, which usually leads to painful abscesses filled with pus. Remarkably, the Staph strains producing these potentially lethal toxins generally produce few of the other proteins normally associated with disease, says Dr. Novick. (The symptoms of toxic shock syndrome, according to the Centers for Disease Control and Prevention, are a fever of 102 degrees, very low blood pressure - which can be fatal - and a sunburn-like rash that peels within two weeks of the onset of other symptoms.)
"In other words, Staph has at least two different ways of interacting with its victim," says Dr. Novick. "It can act locally by attacking tissue and causing classical abscesses, or alternatively, it may produce a potent toxin that is absorbed into the bloodstream and travels throughout the body, damaging various organs, with a possibly fatal outcome. The surprise is that the toxic shock toxin itself flips the switch between these two modes of infection, by turning down the production by the bacteria of the other proteins that contribute to the infectious process, an effect that we could never have anticipated."
"There are lots of bacterial toxins around but none has been shown to regulate or repress genes in the bacterial cell," says Dr. Novick. "This was quite a surprising results and is brand new; yet it does make sense from the point of view of the bacterium - why waste energy and resources producing all the other toxic products when this single toxin will do the job?"
Dr. Novick said that in future experiments his team hopes to characterize how the toxic shock toxin regulates the bacterial genes responsible for purulent infections, to investigate whether other types of superantigens have similar regulatory roles, and to determine how the organism behaves in the tissues.
This study was supported by grants from the National Institutes of Health.
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