Paving way for better treatment

SCIENTISTS HAVE completed sequencing the genome of Streptococcus pyogenes, a bacterium that causes a wide variety of human diseases. The "rap sheet" on this organism, also known as group A streptococci or GAS, stretches long: GAS infection can lead to strep throat, scarlet fever, the skin infection impetigo, pneumonia, acute kidney inflammation, toxic shock syndrome, blood "poisoning," acute rheumatic fever, rheumatic heart disease, and the flesh- eating disease known as necrotizing fasciitis.

"This exceptionally virulent organism is difficult to study because it infects only humans and very few animal models of group A strep diseases exist," says Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). "We need to know more about how group A strep interact with humans to cause so many different illnesses. The genetic sequence should shed light on these questions and pave the way for better treatment and prevention."

"Infection with this bacterium occurs worldwide, and acute rheumatic fever is the major cause of heart disease in children of developing countries," says Fran Rubin a respiratory diseases program officer at NIAID. "This is one reason why sequencing this organism is so critical." Several million cases of strep throat and impetigo occur each year in the U.S.

In addition, in 1999 GAS infection led to 9,400 more serious illnesses such as toxic shock syndrome or necrotizing fasciitis in the United States. These invasive diseases occur when GAS get into parts of the body where bacteria are not usually found, such as the blood and muscles. The sequencing project, supported by NIAID, was carried out by researchers at the University of Oklahoma Health Sciences Center. Their findings appeared in the the Proceedings of the National Academy of Sciences.

The single, circular chromosome containing the bacterium's genetic material is more than 1.8 million DNA base pairs long, reports a molecular biologist at the University of Oklahoma and head of the genome sequencing team. The particular strain of S. pyogenes that researchers examined, designated SF370, was isolated from the infected wound of a patient and can cause invasive diseases such as streptococcal toxic shock syndrome or necrotizing fasciitis. Preliminary analysis of its estimated 1,752 genes includes the following observations:

The genome contains more than 40 possible virulence genes. "We didn't know about the existence of many of these genes," said Ferretti. "This new knowledge will broaden our understanding of how this organism causes disease."

Specific genes may allow GAS to mimic certain molecules in people it infects. For example, one GAS gene codes for a protein similar to the collagen found in human connective tissue. Ferretti speculates that when the immune system attacks this streptococcal protein, it may also mistakenly attack connective tissue, resulting in rheumatic fever.

The genome contains four sections inserted by bacteriophages, viruses that infect bacteria and splice their genes into the bacterial DNA. Some of these virally acquired genes code for "superantigen-like proteins," which can provoke immune system responses that lead to toxic shock.

The presence of these viral genes strongly suggests that bacteriophages can spur GAS to evolve into new and more dangerous strains, Ferretti says. The sequence information should aid efforts to develop vaccines against GAS, notes Rubin. NIAID- supported research has led to the development of several GAS vaccine candidates in various stages of testing.

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