Immune genes determine outcome of strep infection. (Life or Death).

Think of it as Russian roulette with a bacterium instead of a gun. Most people infected with group A streptococcal bacteria notice no symptoms or simply develop a sore throat. Sometimes, however, a strep infection erupts into a life-threatening illness, causing failure of several organs and shock. On even rarer occasions, the infection devours a person's flesh at a remarkable rate.

Subtle variations among people's immune genes may largely account for the radically different outcomes, according to an international team of researchers led by Malak Kotb of the University of Tennessee in Memphis. Curiously, the immune-gene types that produce the strongest reaction to the strep A bacteria seem to also predispose people to the most-severe disease.

The scientists focused on genes encoding cell-surface proteins called human leukocyte antigens (HLAs). On certain immune system cells, these molecules present bits of microbes to other immune cells and prod them to respond. People have evolved many different forms of HLAs, making individuals more or less susceptible to various infections.

In the case of strep A infections, the bacterium secretes toxic proteins called superantigens that bind to HLAs. The superantigens seem to overstimulate the immune system and thereby prevent an effective tailored response to the bacterium, says Kotb.

As reported in an upcoming Nature Medicine, Kotb's team examined the HLA genes of two groups, each of more than 250 people. The participants in one group had strep A infections of varying severity and in the other group, were healthy and uninfected.

The researchers found that certain combinations of HLA-gene variants were underrepresented or overrepresented in various patient categories. From those data the team pinpointed a combination of two variants that seems to protect people with strep A infections from developing organ failure and shock. The scientists also identified a pair of variants that appears to make people more susceptible to an organ-damaging infection. Finally, the researchers detected a pair of variants that protects people from the flesh-eating symptoms of strep A infections but not organ failure.

Kotb and her colleagues also exposed white blood cells from their volunteers to the superantigens produced by strep A. The blood cells of people with HLA genes that protect against organ failure responded less strongly than did the cells of people with HLA genes that increase the risk of a life-threatening strep A infection.

This indicates that a body's exaggerated immune response, a flood of cells and inflammatory chemicals, causes the most dangerous symptoms of strep A infection. "The host is actually harming itself," says Kotb.

Because a medical test can determine the HLA type of a person in just an hour, physicians may someday routinely use HLA type to decide how aggressively to treat a person with strep A infection.

Victor Nizet of the University of California, San Diego says that the new findings also set the stage for identifying exactly which strep A superantigens trigger disease, results that may lead to new drugs or a vaccine.