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Discovery of key protein’s shape could lead to improved bacterial pneumonia vaccine

22.12.2004


St. Jude finding gives insights into how pneumonia bacteria ‘hijack’ a molecular shuttle that carries antibodies from the bloodstream and use this shuttle to invade the body



Scientists at St. Jude Children’s Research Hospital have discovered that the shape of a protein on the surface of pneumonia bacteria helps these germs invade the human bloodstream. This finding, published Dec. 16 online by the EMBO Journal, could help scientists develop a vaccine that is significantly more effective at protecting children against the disease.

The St. Jude researchers determined the shape of a large, paddle-like molecule that Streptococcus pneumoniae bacteria use to latch onto cells lining the throat and lungs. The protein, called CbpA, binds to a molecule on the cell called pIgR, which takes antibodies from the bloodstream on one side of the cell and transports them to the other side. There it releases the antibody at the lining of the throat and lungs. If a pneumococcus bacterium is hovering on the lining of the respiratory tract, this germ binds to pIgR and pushes this antibody shuttle back through the cell to the bloodstream. Once at the other side of the cell, the pneumococcus breaks free of pIgR and enters the blood, where it can multiply and infect the body.


S. pneumoniae is the only bacterium known to use CbpA to invade human cells by binding to pIgR, according to Richard W. Kriwacki, Ph.D., associate member of St. Jude Structural Biology. Kriwacki is senior author of the EMBO Journal report. "The fact that we now know the structure of this important protein means we can begin to develop a vaccine that is more effective in children than those that are currently available," Kriwacki said.

Elaine Tuomanen, M.D., chair of Infectious Diseases and director of the Children’s Infection Defense Center at St. Jude, is co-author of the EMBO Journal paper.

"Using CbpA as the key part of a new vaccine against S. pneumoniae would solve a problem that now hinders our ability to protect children from this infection," Tuomanen said.

Current pneumonia vaccines designed to protect adults against more than two dozen strains of S. pneumoniae do not work in young children. Adult vaccines are composed of pieces of carbohydrates naturally appearing on the surface of these bacteria. When used in a vaccine, these pieces of carbohydrate stimulate the immune system to make antibodies against the real carbohydrate targets on the bacteria. The problem with such vaccines is that the immune systems of very young children (younger than two years) do not naturally respond to carbohydrates. Pneumococcus vaccines for children must instead be modified by binding those carbohydrates to special proteins that stimulate the immune systems of young children.

"However such vaccines are so complex that they can carry carbohydrate targets for only a few specific strains of pneumonia bacteria," Tuomanen said. "So children are always under-protected, since there are so many different strains of these bacteria."

Knowing the shape of CbpA will guide researchers in their efforts to use part or all of this protein as the basis of a vaccine against S. pneumoniae. "CbpA is a very large protein," Tuomanen said. "Now that we know what it looks like and how it’s put together, we can pull it apart to see if smaller pieces of it can be used to make a vaccine that triggers production of antibodies against the CbpA. Since all the S. pneumoniae strains need CbpA to invade the bloodstream, we can widen the protection of a vaccine to all 90 types of pneumococcus by just adding CbpA, or a piece of CbpA."

The discovery of the structure of CbpA was a two-step process that included studies of how this protein works, followed by determination of its actual structure using powerful laboratory tools.

Previous work by another team suggested that CbpA binds to pIgR. However, that finding was made in "test-tube" experiments without using actual bacteria. So the St. Jude team developed pneumococcus bacteria that had mutated CbpA in order to prove that live bacteria with mutated CbpA could not bind to pIgR on cells. "Our work confirmed that the pneumococcus uses CbpA to bind to human cells," said Beth Mann, a research laboratory specialist in Tuomanen’s lab who developed the bacteria carrying mutated CbpA. Mann, co-author of the paper, also showed that the long, paddle-shaped extensions of the protein must be folded in a specific way in order for CbpA to work.

The discovery of the actual shape of CbpA was made using nuclear magnetic resonance (NMR) spectroscopy and circular dishroism (CD). NMR combines radio wave emissions and a powerful magnetic field to determine the structure of proteins suspended in solutions, while CD measures differences in the absorption of different types of polarized light by molecules to determine their shape. It also can show how that shape can change when the protein interacts with another molecule. "This work required that we develop new NMR methods in order to determine the shape of this protein, which undergoes changes as it interacts with pIgR," said Rensheng Luo, Ph.D., a post-doctoral fellow in St. Jude Structural Biology and Infectious Diseases and first author of the paper.

Other authors of the paper are William S. Lewis, Richard Heath, Siva Sivakolundu, Eilyn R. Lacy (St. Jude); Arthur Rowe (University of Nottingham, Leicestershire, UK); Agnes E. Hamburger (California Institute of Technology, Pasadena, Calif.) and Pamela J. Bjorkman (Howard Hughes Medical Institute, California Institute of Technology).

Bonnie Cameron | EurekAlert!
Further information:
http://www.stjude.org

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