Bacterial Meningitis Impairs Brain’s Housekeeping System

A recently published rat study has found that the brain’s waste management system malfunctions when infected with bacterial meningitis, a life-threatening infectious disease that leaves many survivors with long-lasting neurological impairments.

“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,” says Federico Lovino, associate professor (docent) and group leader at Karolinska Instututet’s Department of Neuroscience. “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.”

First described in 2013, the glymphatic system clears waste from the central nervous system. Several neurological diseases, including Alzheimer’s and Parkinson’s disease, have since been associated with its dysfunction. Now, Lovino and colleagues at Karolinska Institutet in Sweden, University of Texas Health Science Center in Houston and the University of Southern Santa Catarina in Brazil have shown that a malfunctioning glymphatic system allows a buildup of toxic garbage that damages brain cells.

The study—published recently in the journal mBio—examined the glymphatic system in rats infected with the bacteria Streptococcus pneumoniae, the leading pathogen causing bacterial meningitis. The researchers found 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. Over time, increased signs of neuroinflammation and neuronal damage were observed, with a corresponding loss of cognitive abilities.

The team also 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.

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 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.

“It’s like a snowball effect,” Lovino says. “The infection causes a buildup 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.”

Lovino says 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.