July 16, 2002 A common bacterium can turn into a potent killer if it picks up the right set of genes, but how and when those genes are acquired has remained poorly understood. In a new study, researchers show that special viruses are the culprits behind the emergence of virulent select new bacterial strains. Those viruses, called bacteriophages, specifically infect bacteria, capture some of their genes, and transfer the genes from one microbe to the next. By moving genes among their hosts, bacteriophages can create new bacterial strains with potentially deadly properties. The discovery, which will reported this week in the online edition of Proceedings of the National Academy of Sciences, highlights an important mechanism for bacterial evolution and identifies several potential targets for vaccines or drugs to prevent or treat some severe infections.
Group A Streptococcus (GAS) bacteria are common microbes that cause many different diseases, including strep throat, wound infections, toxic shock, "flesh-eating" disease, scarlet fever, rheumatic fever and kidney ailments. James Musser, M.D., Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID), seeks to understand why some GAS strains cause severe infections while others lead to milder illnesses. To accomplish that goal, he and his collaborators have turned to the GAS genome. By comparing the complete genetic blueprints of bacterial strains isolated from people with different GAS infections, the researchers hope to identify specific genes linked with individual diseases.
"We are trying to move past the technical phase of genome research and start using what we have learned from gene sequences to develop new ways to prevent and treat infections and to understand how new, virulent strains emerge," says Dr. Musser, who directs the human bacterial pathogenesis laboratory at NIAID's Rocky Mountain Laboratories in Hamilton, Mont.
In their most recent study, Dr. Musser, Stephen Beres, Ph.D., and their colleagues determined the complete genetic blueprints of a so-called M3 GAS strain isolated from a person with toxic shock syndrome. M3 strains are known for causing extremely invasive infections leading to an unusually high degree of severe illness and death. The M3 strain contains more than 1.9 million pairs of the chemical bases that spell out the bacterium's genetic instructions. Approximately 1.7 million of those bases are shared with other, less deadly GAS strains, leaving about 10 percent of the genome unique to M3. When the researchers looked closely at the unique regions, they found telltale genetic markers indicating that bacteriophages had brought in many of the M3 genes. "What we have discovered is that bacterial viruses have imported crucial new toxin genes to create new virulence strains," says Dr. Musser.
Among the unique genes, the researchers identified several that encode bacterial toxins and enzymes that may contribute to the highly infective nature of M3 GAS bacteria. Amazingly, one of the toxins resembles an enzyme found in potent snake venoms. Those molecules may prove to be useful targets for new drugs, diagnostics or vaccines. The research also opens the door to what Dr. Musser believes is a neglected area of research. "Scientists have known about bacteriophages for a long time," he explains, "but they have not been extensively studied for their indirect contributions to infectious diseases. Now that we have shown their importance to bacterial evolution, there is much we need to know about them."
### Researchers from the University of Minnesota Medical School and The National Jewish Medical and Research Center in Denver also contributed to 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.
SB Beres et al. Genome sequence of a serotype M3 strain of group A Streptococcus: phage-encoded toxins, the high-virulence phenotype, and clone emergence. Proc Natl Acad Sci Early Edition online.
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