Scientists Reveal Secrets of Infectious

Childhood Heart Disease

Researchers have discovered important clues as to why a common bacterium can sometimes lead to a dangerous heart ailment in children. The bacterium, group A Streptococcus (GAS), causes acute rheumatic fever, the most common infectious cause of childhood heart disease in the world. In the United States, it has appeared in several localized outbreaks, and in 1999 the infection and its subsequent heart damage were responsible for 3,600 deaths. But GAS bacteria are relatively common and also cause other diseases ranging from sore throats to toxic shock and "flesh-eating" disease. What makes different GAS strains invade different parts of the body, however, remains largely unknown. In addition, researcher have not known if different rheumatic fever outbreaks are caused by genetically similar bacteria or if different strains can emerge to cause the disease.

By isolating GAS bacteria from a person with the disease, scientists from the National Institute of Allergy and Infectious Diseases (NIAID) have discovered several genes that are unique to those bacteria. Their discovery also reveals that two rheumatic fever outbreaks occurring 12 years apart in the area around Salt Lake City, Utah, were caused by virtually identical GAS strains.

"We have made enormous strides in understanding the biology of infectious diseases, yet much remains to be learned about relatively common bacteria like group A Streptococcus," says Anthony S. Fauci, M.D., NIAID director. "This research reveals some of the secrets of group A Strep and is a major accomplishment in our quest to understand an important childhood disease."

The study was directed by James Musser, M.D., Ph.D., chief of the laboratory of human bacterial pathogenesis at NIAID's Rocky Mountain Laboratories in Hamilton, Mont. Dr. Musser and his colleagues determined the genetic blueprint of a GAS strain taken from a patient with rheumatic fever. Many GAS bacteria that cause that disease are called M18 strains. The researchers then compared the M18 GAS blueprint to the DNA sequence of a non-M18 GAS strain, which does not cause the disease.

The researchers discovered several key differences between the two bacterial isolates. Although the M18 and non-M18 bacteria contained many of the same genes, the M18 strain had additional genes that encode novel bacterial toxins that profoundly alter the human immune system. In addition, most regions of gene variation between the two strains appeared to come from phages, viruses that can invade bacteria and insert large numbers of genes into the bacterium's own DNA. The presence of "swappable" toxin genes has important implications for understanding GAS outbreaks because it provides a mechanism for bacteria to exchange genes among themselves and readily breed new virulent strains.

To see if individual GAS bacteria had different combinations of those genes, the researchers analyzed 36 strains isolated during different rheumatic fever outbreaks from different parts of the country. Those strains showed little or no genetic variability. In particular, the study showed that GAS bacteria isolated from patients during the 1998-1999 Salt Lake City outbreak were nearly identical to those isolated from patients during the 1986-1987 epidemic in the same area. Therefore, the later outbreak appeared to be caused by a resurgence of the bacteria that caused the earlier cluster of illnesses, not by a new strain invading the area.

The results of these studies establish a much-needed framework for rapid advances in rheumatic fever research. They not only identify key features to the evolution and spread of rheumatic fever, but also establish potential new bacterial proteins that might prove useful as targets for new drugs and diagnostic tests.

Researchers from Geospiza, Inc., Seattle, Wash., the University of Minnesota, and Primary Children's Medical Center in Salt Lake City also participated in this study. NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

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Reference:
JC Smoot et al. Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with acute rheumatic fever outbreaks. Proceedings of the National Academy of Sciences Early Edition online, March 26, 2002

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site athttp://www.niaid.nih.gov.

NIAID is a component of the National Institutes of Health (NIH), an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.