Researchers at Yale have identified multiple pathogenic "alien islands" in the genome of the A. baumannii, bacteria that has been responsible for new and highly drug-resistant infections in combat troops in the Middle East, according to a report in the March 1 issue of Genes and Development.
"Drug resistant bacterial infections are a rapidly growing problem in hospital settings, and now in difficult conditions of combat. We targeted A. baumannii as a growing threat for our troops in Iraq," said s principal investigator Michael Snyder, the Lewis B Cullman Professor of Molecular Cellular & Developmental Biology. "Having the genome sequence of this microbe is critical for understanding how it harms humans."
A. baumannii causes infections such as pneumonia, meningitis, sepsis and urinary tract infections. Although it rarely causes infection in healthy individuals, persons with diabetes, chronic lung disease, or with compromised immune systems are at increased risk.
The bacterium has been isolated from soil and water, as well as the skin of healthcare workers, and hospital-acquired infections due to A. baumannii have been associated with a mortality rate as high as 75 percent. Recently an outbreak of blood stream infections with drug-resistant A. baumannii was reported in over 240 troops in Iraq.
The DNA sequence analysis of A. baumannii revealed several important features including some that may allow researchers to design better drugs to treat infection. A surprising 17 percent of the DNA that codes for protein in this microorganism is present in "alien islands," or sequences that originated in other microorganisms.
"It is like an old pair of jeans--no pun intended--which have been patched so many times that the patches represent a significant portion of the structure," said Snyder. "Although not originally part of the organism, these 'alien island' sequences have become integrated into the A. baumannii DNA and now represent a significant portion of that genome."
Bacteria typically acquire alien DNA from other microorganisms through a process known as "horizontal gene transfer," and alien DNA is more likely to be retained and passed down to next generations of bacteria when it provides a survival benefit. This study reported that 16 of the presumed 28 alien islands in A. baumannii, contain genes implicated in virulence.
Two of the alien islands identified contained genes that did not match known sequences in the databases. The experiments showed that genes in those islands were important for virulence by a selectively inactivating them and causing a loss of virulence. The authors suggest that these newly identified virulence genes may be good targets for antimicrobial drug development in addition to providing insight into the way organisms evolve virulence.
The researchers used a combination of cutting-edge technologies, including the high-density DNA pyro-sequencing process developed by 454 Life Sciences and functional screening via transposon mutagenesis. Using this process the genome of a comparable microbe could be sequenced and analyzed completely in only a few weeks, according to Snyder..
Michael Egholm, vice president of research and development with 454 Life Sciences, said, "454 Sequencing allows the rapid elucidation of the DNA sequence of any microbe and, when combined with gene function screens, can identify many novel genes important for microbial pathogenesis." 454 Life Sciences has made its technology commercially available via the 454 Sequencing Center, which offers sequencing services to clients worldwide.
According to Snyder, "The new 454 Sequencing technology allows any lab to be able to efficiently sequence a bacterial genome at high quality. In fact, a bacterial genome can be now sequenced and annotated for less than the price of a car."
Other authors on the paper were Michael G. Smith, Tara A. Gianoulis, L. N. Ornston, Mark Gerstein at Yale and Stefan Pukatzki and John J. Mekalanos at Harvard. This research was supported by funds from the National Institutes of Health, the Burroughs Wellcome Foundation, and the American Cancer Society.
Citation: Genes and Development (March 1, 2007)
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