(group B , GBS) and (SP) are the leading pathogens of bacterial meningitis in newborns and infants, respectively (1). GBSAbout one-third of all cases of meningitis in preterm infants and newborns are caused by GBS, while approximately half of meningitis in older infants is attributable to SP, in particular, in developing counties (2). Several studies have shown that neuronal vulnerability is extremely high in the first week of life and thus vulnerable to infection (3). During this time, there are crucial developmental processes that form the basis of the brain network. Without this development, brain function can be severely limited. During meningitis, the bacteria kill cells and release their fragments causing irreparable harm. Although mortality of meningitis in the very youngest age groups has dropped significantly, especially in developed countries, long-term neurological deficits such as deafness, blindness, cerebral palsy, seizures, hydrocephalus or cognitive impairment has remained virtually unchanged in 25%–50% of survivors(1).
First, they injected rats with regular GBS bacteria and mutant GBS bacteria that is cytolysin deficient and looked for differences in the increase of leukocytes. However, no differences were found prompting the researchers to look at apoptotic cells (cells that are dying) in the cerebral spinal fluid (the fluid that supplies nutrients to the brain and spinal column). They found that meningitis induced by either GBS or SP in neonatal rats caused a significant increase of apoptotic cells in the cortex (key role in memory, attention, thought, language, and consciousness) and a significant increase of damaged cells in the hippocampus (memory, spatial navigation). The number of apoptotic cells was similar between GBS and SP, however the number of apoptotic cells in the hippocampus was ten times higher than in the cerebral cortex.
The researchers then looked at how the mutant strains of GBS and SP differ from the normal strains in causing neuronal damage. The mutant strains lack the pore-forming cytolysins and pneumolysin in GBS and SP respectively. They found that the mutant strains caused less damage in the hippocampus and the cerebral cortex than the normal strains. Additionally, when the researchers knocked out (genetically mutated) HO in the SP mutant, further reduced neuronal damage. This data indicates that these pore-forming complexes are essential for meningitis caused cell death and neuronal damage.
They then tested the effects of cytolysins on neurons in culture assays. Neurons were exposed to different concentrations of cytolysins for different periods of time. The cytolysin, as expected, caused apoptosis in a time and concentration dependent manner (the longer the neuron is exposed and the higher the concentration, the more apoptosis observed). They also saw a shrinkage and fragmentation of mitochondria which is the cell’s engine. This observation makes perfect sense, because when a pore is formed in a cell, an influx of calcium molecules invades the cell, upsetting its natural balance kept by the mitochondria. This upset causes the mitochondria to essentially stop work thereby killing the cell. They then tried to elucidate the mechanism of apoptosis by looking at caspase-3 activity (one pathway for apoptosis). However, the GBS cytolysin did not induce caspase-3 activity nor did an inhibitor to block caspase-3, block the function of cytolysin.
Then they tested the clinical scores (outward signs of meningitis) to see if there was a different in symptomology between normal GBS and SP bacteria. Both normal bacterial strains exhibited comparable clinical scores therefore there was no significant difference between GBS and SP animals. However, when observing the clinical scores for the mutant GBS and SP bacteria, the resulting scores were significantly better than the normal meningitis causing bacteria. This study found that the bacteria that causes meningitis in both neonatal (GBS) and infants (SP) also causes severe neuronal damage. This damage is caused by certain pore-forming bacterial toxins cytolysin and pneumolysin from GBS and SP respectively. These toxins cause apoptosis in cells in critical areas of the brain, the cortex and hippocampus. However, the apoptosis path has not be elucidated.
1) Reib, Anja et al. Bacterial Pore-Forming Cytolysins Induce Neuronal Damage in a Rat Model of Neonatal Meningitis. J Infect Dis.
1) J. S. Remington and J. O. Klein (ed.), . The W. B. Saunders Co., Philadelphia, Pa. ; -1156.
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