Meningitis sets in when certain bacteria breach the barrier protecting the brain. Uchiyama et al. now identify the key protein that Streptococcus pneumoniae (pneumococcus) uses to penetrate that barrier, unleashing a potentially lethal form of meningitis.
Tightly packed vascular endothelial cells lining the blood–brain barrier block most molecules from entering the cerebrospinal fluid. But certain pathogens can breach this barrier by attaching to endothelial cell receptors and riding to the other side in intracellular vacuoles. Here, Uchiyama and colleagues show that the sialic acid–cleaving surface protein, NanA, attaches the bacteria to human brain endothelial cells in culture and allows the bugs to cross the blood–brain barrier in mice. Blocking NanA prevented cell adhesion and invasion, and plugging NanA into harmless yogurt bacteria allowed these transformed microbes to invade the cultured endothelial cells. Mice infected with wild-type pneumococcus had 16 times more bacteria in their brains than mice infected with a NanA-deficient strain.
The N-terminal lectin domain of NanA bound the protein to the brain endothelial cells. When this domain was blocked or cleaved off, pneumococcus could neither adhere nor invade. The sialic acid–cleaving activity of NanA, which helps the bug colonize the nasal cavity, played only a minor role in brain invasion.
Pneumoccocus has another protein called CbpA that helps the bug adhere to mucosal epithelial cells. Although this protein can also bind to brain endothelial cells, it is mostly hidden on the form of the bacterium that predominates in the bloodstream, according to the authors. Other bacteria express NanA-like proteins, therefore adding these antigens to vaccines could prove to be important in preventing various types of meningitis.