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Untangling the Structure of Lyme Diseaseby Michaela MannThe Department of Energy's National Synchrotron Light Source at Brookhaven National Laboratory helped researchers discover new information about the bacterium that causes Lyme disease. Their work may lead to an effective vaccine and new treatment protocols.
"It's the perfect stealth bacteria," says one frustrated physician. He's talking about Borrelia burgdorferi, the bacterium that causes Lyme disease. This illness, which is often mistaken for diseases ranging from multiple sclerosis to Lupus, can inflict excruciating headaches and muscle pain, affect the brain and nervous system, attack major organs, and inflame joints. Although there have been more than 100,000 reports of the tick-borne Lyme disease in the U.S. since 1982, researchers are still struggling to create vaccines and treatments that are effective against B. burgdorferi. New findings may explain vaccine failure, suggest treatment approaches Investigators are particularly pleased with two recent discoveries made using the Department of Energy's National Synchronous Light Source (NSLS) at Brookhaven National Laboratory. The uniquely refined images they were able to create demonstrated the bacterium changes its outer surface protein according to its host, and that different strains of the bacterium have different electrical charges, which may determine their ability to cause disease. Outer surface, or peripheral, proteins do not penetrate the cell wall and are easily shed, but they are significant in determining a cell's capabilitiesfor example, how it attaches to other cells or survives in specific environments. "These findings make it clear what direction the research should take," says John Dunn, a biologist and principal investigator at Brookhaven National Laboratory. "There's a lot of work left to do, but now we have a much better sense of where we should be looking." Researchers from Brookhaven, Stony Brook University's School of Medicine, the University of Rochester medical Center, and Rutgers University reported their findings on the OspC structure in the March 1, 2001 edition of the EMBO Journal. Altered surface proteins
This switch may explain some of the problems encountered with the original Lyme disease vaccine, which was developed to counteract OspA. Vaccines that confer active immunity, such as the OspA vaccine, are very specific and stimulate the immune system to attack invading cells that exhibit a particular protein. Because B. burgdorferi does not exhibit OspA in the human body (or exhibits it weakly), the immune system of the vaccinated person doesn't "recognize" the bacterium. Invasive bacterium may pack a negative charge
Further, the invasive bacteria appear to share a common trait: they all have a strong negative charge in the area of the OspC dimer. The researchers postulate that this negative charge may help the bacterium attach to cell tissue, which carries a more positive charge. "Understanding the correlation between surface charge and invasiveness may be useful not only in developing an effective vaccine, but also in predicting whether other OspC bacterium are likely to cause disease," said Subramanyam Swaminathan, another member of the Brookhaven research team. Understanding the structure is the key It is no easy matter to concoct fragile organic matter, such as protein chains, into crystals that can withstand the powerful radiation bombardment of the NSLS and yet retain their original structure. To do this, the Brookhaven team drew upon available nuclear magnetic resonance (NMR) information to identify the least stable areas of the OspC proteinthe C and N termini. They truncated the protein to remove these termini and improve their chances of crystallizing portions of the protein into a stable, viewable form. They then expressed and purified the protein to ensure homogeneity, and grew them as crystals. These crystals were frozen to liquid nitrogen temperature and then illuminated with the NSLS beams. By varying the wavelength of the light beams and by using a technique called multiple wavelength anomalous diffraction (MAD), the researchers generated more than 120,000 different "reflections" (diffraction patterns). Using computer-assisted analysis and visual imaging techniques, researchers resolved the diffraction patterns into vivid 3-D views of both the shape and surface characteristics (such as the charge) of that portion of the OspC protein. Once the basic shape of the proteinhow it "folds"was determined for two of the invasive OspC groups, the researchers used computer modeling techniques to infer the structure of the remaining 17 groups, considerably speeding the investigative process. The technique and findings are discussed by Swaminathan and fellow researchers in the March 2001 edition of Acta Crytallographica, D57. This information about structure and the techniques used to derive it are expected to prove significant in understanding the behavior of other disease-causing bacteria. The next step, developing an OspC vaccine, is not a simple task. However, says Dunn, having the structure of the OspC protein is a major step forward. Media contacts: Diane Greenberg, BNL, (631) 344-2347, greenb@bnl.gov
Related web links from DOE's Virtual Resource Library: Funding: The National Synchrotron Light Source, at Brookhaven National Laboratory in New York, is a national user research facility funded by the U.S. Department of Energy's Office of Science, Division of Basic Energy Science. The NSLS operates two electron storage rings: an X-Ray Ring and a Vacuum Ultra Violet (VUV) Ring which provide intense focused light spanning the electromagnetic spectrum from the infrared through x-rays. |
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