Study Finds Bacterial Antigen Critical in Lethal Effects of Infection, Provides Clues for Therapy

A predominant molecular cause underlying lethal forms of infective endocarditis, sepsis, and kidney damage that often result from Staphylococcus aureus infection has been found, as well as indications for prevention and treatment therapies.

According to a study by a collaborative team at the University of Iowa (Iowa City, Iowa, USA) and the University of Minnesota (Minneapolis, MN, USA), the major superantigen (SAg) produced by S. aureus, staphylococcal enterotoxin C (SEC), is also a major cause of these severe conditions. Using the methicillin-resistant S. aureus (MRSA) strain MW2, the team showed that lethal sepsis, infective endocarditis and acute kidney infections in rabbits are critically dependent on high-level SAgs. SAgs, particularly SEC, were found to have a critical role in the development of all three conditions and that the association results from both superantigenicity and direct toxic effects on endothelial cells, the latter likely contributing to delayed endothelium healing. In contrast, the isogenic strain lacking SEC was found to be attenuated in virulence, and complementation with SEC restores disease production.

Infective endocarditis resulting from staph infection has a mortality rate of about 40%–50%, and about half of the surviving patients will suffer a stroke. The study showed that SEC not only over activates the immune system, but that this “excessive immune response is actually contributing very significantly to the destructive aspects of the disease, including capillary leakage, low blood pressure, shock, fever, destruction of the heart valves, and strokes that may occur in half of patients," said Patrick Schlievert, PhD, professor and chair of microbiology at the UI Carver College of Medicine. In addition to effects of excessive immune response, the SAgs also appear to have direct toxic effects, in part via endothelial cell stimulation.

Treatment therapeutics and prevention by vaccination are potential strategies for blocking these harmful effects. "We have high affinity molecules that neutralize superantigens and we have previously shown in experimental animals that we can actually prevent strokes associated with endocarditis in animal models. Likewise, we have shown that we can vaccinate against the superantigens and prevent serious disease in animals," said Prof. Schlievert. Also, low blood flow via the infection site appears to be one of the consequences of SEC’s action. The team found that increasing blood pressure by fluid replacement therapy reduced the formation of vegetations (the plaque-like meshwork made up of bacteria and host cell factors) on the heart valves and significantly protected from infective endocarditis, possibly also by washing away significant amounts of the superantigen molecule itself.

The study was published online August 20, 2013, in the American Society for Microbiology journal mBio.

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University of Iowa
University of Minnesota
US National Institutes of Health