Key Point

Researchers have recently discovered the mechanism by which S pneumoniae enters the bloodstream. This may aid in developing more effective, less costly pneumococcal vaccines.

MEMPHIS—Streptococcus pneumoniae is the most common bacteria that can lead to hospitalization in all age-groups, but primarily the very old and very young. The emergence of antimicrobial resistance has increased the need for new therapeutic options. Recently, investigators at St. Jude Children’s Research Hospital in Memphis, together with others from the University of Nottingham in the United Kingdom and the California Institute of Technology in Pasadena, determined the shape of a large, paddle-like protein that S pneumoniae bacteria use to latch onto cells lining the throat and lungs.¹

The protein—choline-binding protein A (CbpA)—binds to a molecule on the cell called polymeric immunoglobulin receptor (pIgR), which takes antibodies from the bloodstream on one side of the cell and transports them to the other side, where the antibody is released at the lining of the throat and lungs. If a pneumococcus bacterium is hovering on the lining of the respiratory tract, it uses CbpA to bind 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 bloodstream, where it can multiply and infect the body.

Using nuclear magnetic resonance spectroscopy, the investigators determined that CbpA has an unusual structure comprised of three antiparallel α-helices that bundle together into a raft-like structure. The CbpA structure reveals the conformation of a conserved hexapeptide (YPT) motif and a tyrosine fork—located near the loop between helices 1 and 2—that are required for its binding to pIgR and for S pneumoniae to enter the bloodstream. This study confirmed previous indications that the pneumococcus uses CbpA to invade cells in the human body.

BUILDING A BETTER VACCINE

The observation that CbpA is highly conserved “suggests that a vaccine developed against the conserved features of CbpA—specifically the R2 domain whose 3D structure was determined—may be broadly effective in protecting humans against pneumococcal disease,” explained Richard W. Kriwacki, PhD, Associate Member of the Department of Structural Biology at St. Jude Children’s Research Hospital.

Currently, pneumonia vaccines that can protect adults against more than 23 different strains of S pneumoniae are not effective in young children, whose immune systems cannot respond to the vaccine’s complex ingredients. In addition, said Dr. Kriwacki, “the vaccine that is somewhat effective in young children only targets seven pneumococcal strains. Because it is based on capsular polysaccharides conjugated to carrier protein, it is also expensive to manufacture and therefore receives limited use in the developing world.” He and his colleagues have theorized that using CbpA as the key component of a new vaccine against S pneumoniae could solve these problems.

“CbpA is a very large protein,” pointed out Elaine Tuomanen, MD, who is Chair of Infectious Diseases and Director of the Children’s Infections Defense Center at St. Jude. “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,” she said. “Since all of the S pneumoniae strains need CbpA to invade the bloodstream, we can widen the protection of a vaccine to all 90 types of pneumococcus just by adding CbpA, or a piece of CbpA.”

—Gale Jurasek

Reference
1. Luo R, Mann B, Lewis WS, et al. Solution structure of choline binding protein A, the major adhesin of Streptococcus pneumoniae. EMBO J. 2005;24:34-43.

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