Understanding a Deadly Brain Infection

Scientists thought they knew the cause of acute viral meningitis, until Scripps Research Associate Professor Dorian McGavern’s team discovered that the assumed culprit was in fact only an accomplice.

“What we thought were the killers are actually immune cells that recruit other accessory cells that then drive the disease,” McGavern explains. “If we can find ways to block recruitment of the cells that actually do the damage into the brain, we may be able to limit the impact of the virus.”

Viral meningitis is a serious, potentially lethal infection that strikes nearly 3,000 Americans annually. Meningitis occurs when the membrane (the meninges) that covers and protects the spinal cord and brain becomes inflamed. The condition is considered a medical emergency because it can lead to an inflammatory response resulting in brain swelling, seizures, blood clotting, epilepsy, or other complications.

Because many viruses are capable of causing meningitis, McGavern’s team selected lymphocytic choriomeningitis virus (LCMV) to use in their study because it does not cause much damage by itself. Instead, it is the immune response that the virus activates which damages the brain by creating “leaky” blood vessels in the meninges at the blood-brain border. “We use this mild virus because all the damage in the brain is caused by the immune system,” McGavern says.

Researchers were then able to employ a method devised by New York University scientists that allows researchers to “watch” what happens in the brain of mice infected with the virus by tagging targeted cells with proteins that shine a fluorescent green. Their targets were immune cells called cytotoxic T lymphocytes, also known as killer T cells, which were previously thought to be responsible for battling the virus and damaging the brain in the process.

As they watched the blood cells breaking down as the meningitis developed and progressed, however, the researchers were surprised to see that the killer T cells did not appear to be the direct cause of the damage.

“We thought the disease depended on these killer T cells, but they didn’t seem to be associated with any of the damage we were seeing,” McGavern said.

To investigate further, the researchers then tagged other populations of immune cells: monocytes, which clean up and repair damage, and neutrophils, which may help with antiviral immunity. To their surprise, the scientists saw that these cells flooded the brain after LCMV infection, and were associated with significant damage to blood vessels in the brain’s membrane.

“The vessels just start exploding,” McGavern explains. “This tells us that killer T cells recruit monocytes and neutrophils that actually produce the pathology we see with meningitis. What we thought were the cells responsible actually only recruit accomplices who commit the crime.”

Many questions, however, still remain. Researchers don’t know exactly why monocytes and neutrophils are called to the sites of infection by killer T cells, or how they produce such damage. They theorize that the breakdown of blood vessels may be the result of the cells’ attempts to move quickly out of the blood system into tissue within the confined space of the brain.

With a new avenue to explore for possible treatments for the deadly disease, McGavern and his team are poised for further discovery. Your gift to Scripps Research can help ensure that the team makes the next big step in scientific understanding of this deadly infection.