New-found impact of meningitis on brain
Image: Meningeal macrophages (shown in white, red, and blue) are on constant alert against potential threats to brain tissue. [McGavern Lab, NINDS]
New results from researchers at the US-based National Institute of Neurological Disorders and Strokes reveal that meningitis changes the immune cell make-up in the lining of mouse brains.
During a virus attack, immune cells from within the meninges - the protective layers covering the brain and spinal cord - are replaced with cells from outside this lining that become less likely to resist future attacks.
As Dr Dorian McGavern from NINDS says: “After an infection, the immune cell landscape in the brain lining changes. Brain lining immune cells that normally protect the brain from foreign invaders die and are replaced by cells from elsewhere in the body.”
“These new cells are altered in a way that affects how they respond to subsequent challenges and new infections,” he adds.
The meninges of the central nervous system are populated by a dense network of macrophages that act as resident immune sentinels.
Using laser scanning confocal microscopy and two-photon microscopy, McGavern and colleagues studied mouse meningeal macrophages and noted that during normal conditions each macrophage was on 'alert', extending its arm-like pseudopodia and surveying its environment.
They then studied how macrophages changed after infection by lymphocytic choriomeningitis virus, which targets the meninges, causing viral meningitis.
Within two days of the infection, levels of antiviral cytokines increased in the meninges, and after four days, one-third of meningeal macrophages were infected.
Once meningitis has subsided, the researchers went on to investigate the long-term effects of this infection.
Analyses revealed most of the infected macrophages died and were removed from the area by immune cells, leaving a depleted stock of meningeal macrophages.
This supply was refilled by monocytes, immune cells recruited from the blood, some of which eventually turned into macrophages but had different properties from the original cells.
As the researchers discovered, the new macrophages were missing a specific receptor that detects bacteria, making them less effective at responding to future infections.
What's more, the new macrophages also had lower levels of another receptor that recognizes the brain chemical acetylcholine, which normally dulls inflammation in meningeal macrophages.
Consequently, the new macrophages were less responsive to this signal and had trouble quieting an infection-induced inflammatory response.
These results indicate that infections in the brain can have lasting effects, long after the virus leaves the system.
Further studies are needed to learn about additional functions of meningeal macrophages and how these cells respond to other types of viruses and bacteria.
“These findings suggest that in addition to identifying the type of infection, it may also be important to know if it is coming on the heels of an earlier bug because that may affect how the system responds,” adds McGavern. “Getting a virus out of the brain does not necessarily mean that everything goes back to normal.”
Research is published in Nature Immunology.