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UT Health Science Center Scientists Collaborate With International Team to Discover Key to Deadly Flesh-Eating Disease
Memphis, Tenn. (July 18, 2007) – An international team of researchers from The University of Tennessee Health Science Center (UTHSC), University of Wollongong (Australia), University of California, San Diego (UCSD) and Helmholtz Centre for Infection Research (Germany) have discovered an explanation for how a deadly strain of “flesh-eating” bacteria has evolved to produce serious human infections worldwide.
The research, reported July 15, 2007, in an advance online publication of the journal Nature Medicine, focuses on the major human pathogen Group A streptococcus (“strep”). Among the most important of all human infectious disease agents, strep is responsible for a wide range of diseases, ranging from simple throat and skin infections to life-threatening invasive conditions such as necrotizing fasciitis (“flesh-eating disease”) and toxic shock syndrome. Strep is estimated to cause more than 700 million infections each year, with more than 650,000 cases caused by dangerous, invasive forms of the bacteria. Largely attributed to the global spread of a single strain of strep known as the invasive M1T1 clone, the incidence of serious strep infections has risen dramatically in the last three decades.
The research group has sought to identify what special characteristics make the invasive M1T1 clone so virulent for humans. Recently, they observed that during the early stages of a simple skin infection, a small subpopulation of the strep bacteria hijacks a protein, called plasminogen, from the human bloodstream, attaches plasminogen to their own surfaces, then activate it into a protease capable of destroying cells and tissues. This sequence of events allows the bacteria to break out and spread through the body. It is now understood that a specific genetic mutation in the M1T1 strep clone controls the shift to this invasive form. This property of the M1T1 strep clone can be traced to an event that occurred about 30 years ago, when a virus known as a bacteriophage infected the strep bacteria and introduced a new gene that allowed the bacteria to resist clearance by the human immune system.
“Just like a computer virus might come in and reprogram your hard drive, this bacteriophage reprogrammed the genetic machinery of the M1T1 strep into a more virulent form,” explained lead author Mark Walker, PhD, a professor of Biological Sciences at the University of Wollongong. “The consequences of this event on human health are still being felt three decades later.”
In key experiments, the research team used genetically engineered mice expressing human plasminogen and infected them with M1T1 strep clone. They discovered that the bacteria routinely mutated, under pressure from the host environment, to the highly invasive form. When the researchers deleted a single bacteriophage gene, the M1T1 strep strain behaved much like its ancestral strain, losing the ability to undergo the dangerous mutation. As a result, it could no longer spread to produce severe infection.
“This is a perfect example of how dangerous forms of microbes can suddenly emerge to cause much more serious diseases than they normally do,” said Malak Kotb, PhD, A. C. Mullins Professor in Research (UTHSC). “In this case the bacteria were infected with a virus, which introduced an important enzyme that made the bacteria much more invasive and more deadly in humans. By understanding how these events occur, we can be better prepared for emerging and remerging infectious diseases, including those that can cause major pandemics.” Dr. Kotb is also a senior research career scientist at the Memphis Veterans Affairs Medical Center and director of the Mid-South Center for Biodefense and Security.
This collaborative study was initiated during Dr. Walker’s Australian-American Fulbright Commission Senior Scholar Award sabbatical in Dr. Kotb’s (UTHSC) and Dr. Nizet’s (UCSD) laboratories, and was financed by grants from the National Institutes of the National Health and Medical Research Council of Australia, and the Department of Employment Science and Technology (Australia) International Science Linkages Program.
As the flagship statewide academic health system, The University of Tennessee Health Science Center is focused on a four-tier mission of education, research, clinical care and public service, all in support of a single goal: to improve the health of Tennesseans. Offering a broad range of postgraduate training opportunities, the main campus, with its six colleges, is in Memphis. UTHSC has additional College of Medicine campus locations in Knoxville and Chattanooga. For more information, visit www.uthsc.edu.
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