Bacterial meningitis is a life-threatening infectious disease of the brain that leaves many survivors with long-lasting neurological impairments. A study in rats by researchers at Karolinska Institutet in Sweden has now shown that the brain’s tool for waste clearance, the glymphatic system, malfunctions during bacterial meningitis, causing a build-up of toxic garbage that damages brain cells.

“Our study shows that the glymphatic system loses its functionality when an infection occurs in the brain,” said Federico Iovino, PhD, associate professor (docent) and group leader at the department of neuroscience, Karolinska Institutet. “Even though we’ve only studied rats so far, we believe it’s possible that the same mechanisms are at play in humans and that the glymphatic system could be a new avenue to explore in the hopes of finding treatments to prevent neurological disabilities caused by bacterial meningitis.”

Iovino is senior author of the team’s published paper in mBio, titled “Dysfunctional glymphatic system with disrupted aquaporin-4 expression pattern on astrocytes causes bacterial product accumulation in the CSF during pneumococcal meningitis.”

The glymphatic system was first described in 2013 as a sort of washing machine that clears waste from the brain and the spinal cord, which comprise the central nervous system (CNS). Several neurological diseases, including Alzheimer’s and Parkinson’s, have been associated with glymphatic system dysfunction. And, as the authors explained, then the fluid dynamics of the glymphatic system are disrupted, “toxic waste accumulates in the brain,” which can exacerbate inflammation and interfere with disease recovery.

Streptococcus pneumoniae bacteria are the primary cause of community-acquired bacterial meningitis, “ … a life-threatening inflammation of the meninges surrounding the brain and spinal cord caused by a bacterial infection of the central nervous system,” the authors explained. The infection can have serious, long-term effects. “In low-resource countries, persistent cognitive impairment is estimated to occur in 4–41% of children who survive an episode of pneumococcal meningitis. And in adults who survived pneumococcal meningitis in high-resource countries, cognitive impairment is estimated to occur in 32% of survivors.

“About half of pneumococcal meningitis survivors suffer from neurological impairments, such as hearing loss, motor and cognitive delay, and psychiatric disorders, because of neurons damaged by the infection,” Iovino commented. “Since damaged neurons often cannot be repaired or replaced, it is important to find ways to prevent the injury, and the first step in that direction is to understand the molecular mechanisms.”

The inflammation triggered by the host immune response to S. pneumoniae infection leads to the recruitment of peripheral immune cells into the brain and the cerebrospinal fluid (CSF) to eliminate invasive pathogens, the team noted. Inflammatory mediators released in the brain during the infection include cytokines, chemokines, reactive oxygen and nitrogen species, and neurotoxic molecules that contribute to the activation of the microglial cells, initiating neuroinflammation. And as they pointed out, “All these waste products, including host-derived debris, the invading pathogen itself, and any secreted toxins, are released in the CSF and brain parenchyma and must be efficiently cleared from the brain to regain CNS homeostasis.”

For their reported study, the Iovino lab research group and collaborators at the University of Texas Health Science Center and the University of Southern Santa Catarina examined the glymphatic system in rats infected with S. pneumoniae. The study, they said, “ … hypothesized that pneumococcal meningitis impaired the glymphatic system’s functionality, decreasing neurotoxic waste clearance in the brain.”

The investigators’ analyses showed higher amounts of bacterial waste products in the brains of rats with meningitis than in a control group. The concentrations were highest in the brain’s cerebrospinal fluid compartments. In contrast, blood tests revealed low levels of bacterial components, indicating the glymphatic system had failed to drain the brain from bacteria and associated rest products. And over time, increased signs of neuroinflammation and neuronal damage were observed, with a corresponding loss of cognitive abilities.

Summarizing the findings of their analyses, the researchers noted, “These results can be explained by the loss of functionality of the glymphatic system, which caused retained accumulation of bacterial components in the CSF…Taking all these findings together, loss of fluid drainage because of a malfunctioning glymphatic system leads to an accumulation of bacteria and bacterial products …”

To further their understanding, the researchers examined brain tissues and cells in detail. They zeroed in on a key fluid transporter, the aquaporin-4 (AQP4)-water channel located at the end-feet of the strings of astrocytes, which are star-shaped cells that act as housekeepers of the glymphatic system. “AQP4-water channels are a fundamental component of the glymphatic system, facilitating solute transport from the perivascular subarachnoid space and the brain parenchyma.”

This water channel normally regulates fluid exchanges between the cerebrospinal fluid compartments and other areas of the brain. But what the researchers found was that during pneumococcal meningitis, the AQP4-water channel lost its natural place and connection with the blood-brain barrier (BBB) vessel wall. The astrocytic end-feet had detached from the vessel walls after the astrocytes swelled in response to the neuroinflammation caused by the bacterial infection.

“Here, we reported for the first time that the impairment of solute transport between perivascular subarachnoid space and the brain parenchyma occurs when a detachment of astrocytic end-feet from the BBB occurs, with consequent misplacement and likely loss of the physiological function of AQP4-water channels of solute transport within the glymphatic system,” the authors stated.

“It’s like a snowball effect,” Iovino said. “The infection causes a build-up of toxic bacterial products, which activates an immune response that leads to neuroinflammation. The inflammation triggers cellular processes that lead to a detachment of astrocytic end-feet from the blood-brain barrier walls with consequent misplacement and loss of function of the important AQP4-water channel. Combined these events result in a malfunctioning glymphatic system and consequent neuronal damage.”

Neuronal injury is frequently seen with neuroinflammation, the authors commented. Damage may be due to direct interaction of the bacteria or bacterial components with the neurons, and as a result of the damaging effects of proinflammatory compounds released during neuroinflammation. “In line with this, associated with a loss of glymphatic system functionality during pneumococcal meningitis pathogenesis, we showed that neuroinflammation and neuronal injury increase over time during the infection. Therefore, our data strongly suggest that the glymphatic system dysfunction could be another factor associated with long-term cognitive impairment in meningitis survivors,” the Iovino team and colleagues stated.

And as they further concluded, the lack of solute drainage due to a dysfunctional glymphatic system leads to an increase of the neurotoxic bacterial material in the CSF compartments of the brain, and this ultimately leads to brain-wide neuroinflammation and neuronal damage, and so impaired neurological function. “The loss of function of the glymphatic system can therefore be a leading cause of the neurological sequelae developing post-bacterial meningitis,” they wrote. “The connections between BBB disruption, glymphatic dysfunction, and cognitive impairment in meningitis survivors could be a new avenue to investigate mechanisms to prevent these events and re-establish an everyday life for these patients committed to bacterial meningitis.”

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