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    Target identified that protects brain from common forms of meningitis

    Elaine Tuomanen

    A team led by St. Jude investigators has identified the cell surface receptor that bacteria and other infectious agents must dupe to launch their assault on the brain, a finding that raises hope for a new generation of meningitis vaccines.

    Writing in the June 1 edition of the Journal of Clinical Investigation, the researchers outlined evidence that the three bacteria responsible for nearly all bacterial meningitis start their journey across the blood-brain barrier at the same receptor. The receptor is on a protein serving as the scaffold for blood vessel walls.

    The target receptor for Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae is on the receptor for the structural protein laminin. Although the three bacteria use different proteins to bind to the laminin receptor (LR), researchers demonstrated the results are the same. When bacteria adhere to the LR, the event triggers a biochemical cascade, opening the door into blood vessel cells. Those endothelial cells provide their route into the brain. Earlier research found other infectious agents, including viruses, prions and bacterial toxins, use the same LR to gain such access.

    Researchers cautioned that other factors are likely involved in helping bacteria across the blood-brain barrier. But evidence of a common receptor raises scientists’ hopes for developing one vaccine against the leading causes of bacterial meningitis. Since viruses and other infectious agents use the same receptor, it might also prove useful for efforts to protect against an even broader array of threats.

    “If you can block the door, you will block a lot of disease-causing organisms of the brain,” explained Elaine Tuomanen, MD, Infectious Diseases chair and the paper’s senior author.

    In the paper, Tuomanen and her co-authors noted that preventing bacteria from adhering to the LR “might engender unexpectedly broad protection against bacterial meningitis and may provide a therapeutic target for the prevention and treatment of disease.”

    The work reflects Tuomanen’s focus on pneumococcus, a leading cause of infection, illness and death among the world’s children. Pneumococcus remain a leading cause of bacterial meningitis, blood stream infections and pneumonia, even though vaccines are available against the most common types of these bacteria.

    Meningitis occurs when bacteria breach the blood-brain barrier, the tight layer of endothelial cells that protect the brain by restricting access to it. Once the bacteria enter the cerebrospinal fluid surrounding the brain and nervous system, they multiply rapidly. The resulting inflammation kills 30 percent of patients and leaves survivors with devastating brain damage.

    These findings build on the earlier work of St. Jude researchers and other investigators to understand how the bacterium moves out from the nose and spreads throughout the body. In the past decade, Tuomanen and others showed the bacteria carry a molecule on their surface that binds to a receptor on the endothelial cells lining blood vessels. The molecule, called phosphorylcholine, mimics an immune component known as a chemokine. Normally the body uses a small protein known as platelet-activating factor (PAF) to attract white blood cells to the PAF receptor. But when phosphorylcholine binds to PAFr on endothelial cells, the cells respond by ushering in the bacteria. Once inside, the bacteria cross into the cerebrospinal fluid.

    This paper describes the first step in the assault on the brain. Investigators wanted to know how pneumococcus bacteria circulating in the blood sticks to the blood vessel walls. In 2005, a St. Jude team demonstrated a surface protein known as CbpA played a key role in allowing pneumococcus to move from the throat and lungs into the blood stream.

    For the current study, the St. Jude investigators crushed blood vessel cells from both rodent and human brains and ran them over beads coated in the bacterial protein. A protein known as 37/67-kDa LR stuck to the beads.

    The scientists traced the binding to a peptide 15 amino acids in length found in a bend of the CbpA protein. By changing just two amino acids, researchers blocked the pneumococcus bacteria from causing meningitis in mice.

    Working with colleagues at the University of Nottingham in the United Kingdom, investigators located LR binding proteins on meningococcus and H. influenzae. In meningococcus, they were the outer membrane proteins PilQ and PorA. H. influenzae used a specialized membrane protein called a porin, in this case OmpP2.

    Bacterial binding to LR, the first step in developing meningitis, prompts the blood-brain barrier endothelial cells to make more PAFr. Such up-regulation made it easier for the phosphorylcholine on the bacteria to use endothelial cells as a portal into the brain. That is the second step in its journey from the blood into the brain.

    Several laboratory and mouse studies underscored the LR’s role. In the laboratory, LR binding fell dramatically when researchers used versions of the three bacteria with the binding proteins either inactivated or missing.

    When microspheres coated with either CbpA, PilQ or PorA were injected into mice, the beads attached rapidly and firmly to the endothelial cells lining blood vessels leading to the brain. The same beads coated with different proteins did not stick. In another experiment, CbpA adherence fell when mice were pre-treated with an antibody to LR.

    “The findings suggest there is a common way to stop the bacteria responsible for the most common forms of meningitis,” Tuomanen said.

    She added that researchers must still determine the biochemical signaling that makes it possible for the bacteria to find this particular LR.

    Other St. Jude authors are Justin Thornton, PhD, and Beth Mann, Infectious Diseases; and Carlos Orihuela, PhD, formerly of St. Jude.

    The research was supported in part by grants from the National Institutes of Health, the James Tudor Foundation and ALSAC.

    July 2009