Why group A strep targets man

The key to the puzzling species specificity of group A streptococci (GAS) is its production of streptokinase, which only activates the blood clot–dissolving factor plasminogen in humans, according to research published in Science this week. The results suggest that this group of organisms, which includes the so-called flesh-eating bacterium—a highly invasive, rapidly progressing, and potentially fatal member of the GAS family that attacks soft tissues and internal organs—evades host attempts at containing infection by breaking down localized defensive blood clots and spreading through the blood stream and into surrounding tissues, according to Hongmin Sun, principal author of the study. Bacterial streptokinase has previously been shown to interact only with the human version of plasminogen to activate its clot-dissolving function. It does not interact with plasminogen from mice or other mammals, suggesting a mechanism for specificity that the team tested by creating what they called "humanized mice" transgenic for the human plasminogen protein. When the mice were challenged with human-specific GAS, they were found to be highly susceptible to infection, said Sun, whose team was headed by David Ginsburg, professor of internal medicine and human genetics at the University of Michigan, Ann Arbor. In addition, plasminogen-binding receptors on the surface of the GAS were critical for invasion through the skin, and the "humanized" mice were again highly susceptible to infection through this route while their normal mouse counterparts were largely unaffected. This suggests an additional mechanism by which the GAS exploit the clot-dissolving system in humans, the authors write. Just why the same bacterium has such a range of afflictions for humans—from relatively harmless throat infections through to the potentially fatal necrotizing fasciitis—is a mystery, according to study coauthor Ulf Sjöbring, who heads a group in the Department of Laboratory Medicine at Lund University. "We really don't know what differentiates them, they are one and the same bacteria, and we can't really say exactly why in some individuals and in some situations you get the very serious manifestations," Sjöbring told The Scientist. But the group's findings raise the possibility that polymorphic variation in the level of plasminogen, and potentially other fibrinolytic components within human populations, could represent a significant susceptibility factor for bacterial infection, he said. However, the study does not prove that plasminogen is the primary host determinant that confers species specificity, Harry S. Courtney, associate professor in the Department of Medicine, University of Tennessee, told The Scientist by E-mail. "There are other virulence factors, such as the streptococcal pyrogenic exotoxins, that do not function well in mice [but that] may also contribute to the species specificity of group A streptococci," said Courtney, who wasn't involved in the study. "I can only say that yes, that is certainly very true," Sjöbring told The Scientist. He said that there is an array of different putative virulence factors produced by GAS, "and if any of those is the virulence factor in, for instance, causing the flesh-eating syndrome—it's very difficult to say and it's very difficult to compare." "The group A streptococcus in general makes its living by expressing 50 to 100 different extracellular proteins that detrimentally affect the human host," said James Musser, chief of the Laboratory of Human Bacterial Pathogenesis at the US National Institute of Allergy and Infectious Diseases, Md., who was not involved in the study. This question of host specificity has been of interest to GAS biologists for many decades now, Musser said. "What's really new is the nice technical strategies that were used to demonstrate that concept." "It's always excellent to be able to demonstrate that a molecule is crucial to virulence, because it adds yet another potential target for therapeutic interventions. This is a very important demonstration that streptokinase may be an important target for therapeutic maneuvers—no question," Musser said.

Why group A strep targets man

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