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Sore throat or toxic shock: It’s in your genes

By Nancy Touchette

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Jim Henson's death in 1990 from a streptococcal infection shocked the world. The creator of the Muppets died just days after being infected by the bacterium best known for causing strep throat.

Around the time of his death, public health officials in the U.S. were monitoring a rise in toxic shock syndrome and flesh-eating disease, caused by the reemergence of pathogenic strains of the Streptococcus pyogenes bacterium. While most infected people experienced little more than a sore throat, others, like Henson, developed severe and potentially fatal illnesses.

Detail of diagram showing superantigen binding to HLA protein complex.

Why was that? The answer may be in how the human body responds to invading bacteria. According to a new study, this response depends on the kinds of genes a person has.

The researchers show that a person's genes are a key factor in whether certain infections cause a mild fever or something much worse. Some people have genes that predispose them to the devastating effects of certain strep infections, while others harbor genes that protect against these consequences.

Malak Kotb of the University of Tennessee in Memphis and her colleagues found that patients born with a certain combination of so-called 'HLA' genes were more likely than other patients to develop toxic shock following an infection by a particular strain of strep.

The key to Kotb's study is that she and her collaborators, Don Low and Allison McGeer at Mt. Sinai Hospital in Toronto, Canada, studied the genes of both the patients and the bacteria infecting them. The findings are published in Nature Medicine.

The researchers also found that patients who have different combinations of HLA genes are prone to flesh-eating disease, or necrotizing fasciitis, in response to the same infection. And yet another combination of HLA genes protects individuals against severe consequences of infection.

"This is very exciting work," says Victor Nizet, an infectious disease specialist at the University of California at San Diego. "Through some really outstanding epidemiological studies combined with the genetic analysis, Kotb and her collaborators discovered a set of genes that were associated with either an increased risk or with protection from severe disease."

For the past several years, researchers have recognized that the virulent strains of strep that have recently reemerged produce special toxins called superantigens.

"Superantigens can cause the cells of our immune system to proliferate and become activated in an uncontrolled fashion," says Nizet. That uncontrolled activation leads to the release of cytokines, a type of signaling molecule that promotes inflammation. It is the exaggerated release of these cytokines that cause the severe symptoms of the invasive disease, he says.

Kotb believes the interaction between the HLA proteins and the superantigens is key to predicting the immune response. Certain HLA proteins have a unique structure that binds superantigens. The superantigens also bind to proteins on immune cells known as T cells. This causes an artificial activation of T cells that triggers an uncontrolled inflammatory reaction throughout the body. The result is toxic shock.

Other HLA proteins adopt a structure that interacts with the superantigen in a way that causes a lower level of inflammation and thus prevents severe disease.

"A superantigen can act like a vice to force the T cell receptors and HLA molecules to interact with each other," she says. "But depending on the combination of certain HLA molecules and superantigens, the inflammatory response can be very high, moderate, or low."

Patrick Schlievert of the University of Minnesota, who first recognized the reemergence of virulent forms of strep in 1987, says the new discovery will help in the treatment of patients infected with Streptococcus pyogenes.

"What is really very interesting about this work is that it will allow us to predict whether someone is infected with a high susceptibility to toxic shock syndrome and a high fatality rate," Schlievert says.

"You would want to treat someone with a high risk for fatality much more aggressively. If you know they are resistant, you don't have that fear."

Kotb, M. et al. An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections. Nat Med Published online November 18, 2002.
Demers, B. et al. Severe invasive group A streptococcal infections in Ontario, Canada: 1987-1991. Clin Infect Dis 16, 792-800 (1993).

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