Researchers find a specific protein on the surface of a common bacterial pathogen allows the bacteria to leave the bloodstream and enter the brain, initiating the deadly infection known as meningitis.
The new finding by scientists in US may lead to the development of improved vaccines to protect those most vulnerable, including young infants and the elderly.
Advertisement"Streptococcus pneumoniae, commonly known as pneumococcus, is responsible for half the cases of bacterial meningitis in humans," said the study's senior author, Victor Nizet, MD, professor of pediatrics and pharmacy at the University of California, San Diego's School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences.
Meningitis develops when bacteria penetrate the "blood-brain barrier."
The blood-brain barrier, comprised of a single layer of highly specialized microvascular endothelial cells, prevents most large molecules from entering into the cerebrospinal fluid, preserving an optimal biochemical environment for brain function.
The research team examined the functions of a protein known as NanA in order to discover how an entire bacterium can breech the blood-brain barrier and gain access to the central nervous system.
NanA is produced by all strains of pneumococcus and displayed prominently on the bacteria's outer surface.
Through genetic manipulations, the researchers were able to remove the entire NanA protein, or just specific sections of the molecule, from the pathogen.
They found that while normal pneumococci were able to bind, enter and penetrate through human brain microvascular endothelial cells, mutant bacteria lacking the NanA protein or those expressing only a truncated version of the protein, largely lost these abilities.
Conversely, when the full-length pneumococcal NanA protein was cloned and expressed on the surface of a nonpathogenic laboratory strain, the transformed bacteria gained the ability to bind and enter the same endothelial cells.
Satoshi Uchiyama, MD, a postdoctoral fellow in the Nizet Laboratory and lead author on the study, said: "Our tissue culture studies showed that the NanA protein was both necessary and sufficient for bacterial penetration of the blood brain barrier endothelial cells."
"After infecting mice intravenously, we also found that far fewer NanA-deficient bacteria left the bloodstream and entered the brain, in comparison to mice infected with the normal pneumococcus," Uchiyama added.
NanA is best known as an enzyme that cleaves and releases the sugar molecule known as sialic acid, which is present in abundance on the surface of all human cells.
While this enzymatic activity played a small part in promoting NanA-mediated blood-brain barrier interactions, a much stronger role was identified for the outer tip of the protein.
This tip seems to directly attach to the brain microvascular endothelial cells and then stimulate them to take in the pneumococcus.
According to Nizet, because NanA is expressed on the surface of all pneumococcal strains, it is an attractive candidate to include in a universal protein-based vaccine against pneumococcal infection.
The study is available online in the Journal of Experimental Medicine.
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