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A tiny, green tree frog spots lunch on a branch above its head. Its four legs suction their way to the top leaves—one leg at a time. It’s a methodical climb—each toe grasping a different part of the branch. Little does the frog know of its similarity to one of the largest bacterial molecules to attack the human body.
In 1997, researchers at St. Jude Children’s Research Hospital discovered a protein on the surface of pneumonia bacteria that allows the bacteria to attach to human cells. It’s called choline binding protein A or CbpA. Recently, St. Jude investigators discovered that the protein’s shape—large and paddle-like—helps pneumonia germs attach to cells that line the throat and lungs and ultimately invade the bloodstream.
“It’s big, it’s complicated, and it has many arms,” says Elaine Tuomanen, MD, Infectious Diseases. “It can attach to different cells using one or the other of those arms in a sequential manner. CbpA is critical to first getting a bacterium into a person and then moving that bacterium from the nose into the lungs, from the lungs to the blood, and then to the brain. Think of a tree frog jumping from one kind of cell to another to another and sticking to it with its suction cups.”
CbpA binds to a molecule on the cell called pIgR, which transports antibodies made inside the body across cells, releasing them on the surfaces of the nose and lungs. If a pneumococcus bacterium is hovering on the respiratory tract’s lining, this germ binds to pIgR and pushes it back through the cell to the bloodstream. Once on the other side of the cell, the pneumococcus breaks free of pIgR and enters the blood, where it can multiply and infect the body. Streptococcus pneumoniae is the only bacterium known to use CbpA to invade human cells by binding to pIgR.
The fact that CbpA targets a number of different cell types makes it useful to St. Jude researchers. “If we know how to get rid of the function of the protein, then we could very reasonably imagine how to make a highly immunogenic vaccine that would be broadly protective,” Tuomanen says. “That is our aim.”
Tuomanen worked closely with Richard Kriwacki, PhD, Structural Biology, to try to understand how each of the “suction cup fingers” on CbpA works.
“We got a bird’s-eye view of the molecule showing where all of its corners and crannies were,” Tuomanen says. “Knowing the structure of it helps us point to areas that could function as bridges linking the bacteria to the human cell. Imagine the number of different possibilities.”
The discovery of CbpA’s shape will guide researchers in their efforts to use part or all of this protein as the basis of a vaccine against Streptococcus pneumoniae.
“The fact that we know the structure of this important protein means we can begin to develop a vaccine that is more effective in children than those currently out there,” Kriwacki says. “In addition, by understanding the structure of these domains of CbpA, we now understand the molecular basis for the attachment of pneumococci to human cells. It is an important first step in discovering drugs that would specifically disrupt this attachment process.”
The broadest pneumonia vaccine, designed to protect against 23 of the 90 kinds of Streptococcus pneumoniae, does not work in younger children because their immune systems do not naturally respond to the bacterial sugars that make up the vaccine. Pneumococcal vaccines for children must instead be modified by binding those sugars to special proteins that stimulate the children’s immune systems.
“Such vaccines are so complex that they target only a few specific strains of pneumonia bacteria,” Tuomanen says. “So children are always under-protected. Our discovery of CbpA’s shape has the possibility to make another generation of vaccine where the protein needed to alert the immune system of children is broadly represented in almost all pneumonia strains.”
Respiratory infections are the No. 1 killer of kids in the world. These kinds of infections are also often fatal in children whose immune systems have been suppressed by cancer treatment or other therapies. Each year in the United States, pneumococcal disease causes 3,000 cases of meningitis; 5,000 cases of pneumonia and 7 million cases of ear infection. “The number of children who die of pneumococcal infection worldwide is astronomical,” Kriwacki says.
With the opening of the GMP at St. Jude—of which Tuomanen was instrumental—the hospital now has an effort to modify the vaccine development process further and faster.
“I’m particularly proud of the fact that several groups in the Children’s Infection Defense Center at St. Jude are working on vaccines and they have used the GMP to accelerate development of new therapeutics for orphan infections in kids. It expands the St. Jude mission from the bench to the bedside to the context of infectious diseases,” Tuomanen says. “When you think about the enormity of preventing just ear infections—the most common reason a child goes to the doctor—then you see that this type of a vaccine could have a really big impact.”
Reprinted from Promise magazine, autumn 2005
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