The link between viral meningitis and fatal seizures

NYU Langone Medical Center scientists have announced the discovery of an unexpected cause for the fatal seizures seen in mice with viral meningitis, an infection of the central nervous system.

The researchers say that their breakthrough may lead to a new way of thinking about how the human immune system responds to viral diseases. Research leaders Dr. Michael L. Dustin and Dr. Jiyun V. Kim employed intravital two-photon microscopy to peer inside the skulls of infected mice. They said that their breakthrough technology could be used to take moving pictures of immune cells in action.

According to them, the cells are tagged with a protein that glows fluorescent green when activated by infrared light, which is able to penetrate living tissue without damaging it. The researchers joined forces with Dr. Dorian McGavern, Associate Professor of Immunology, and Dr. Silvia Kang at Scripps Research Institute, who provided virology expertise and performed many critical experiments that supported the unexpected findings of the study.

For their study, the researchers used lymphocytic choriomeningitis virus (LCMV), which is relatively harmless in humans with a healthy immune system. They revealed that mice infected with LCMV suffered fatal seizures. The scientists said that they had the idea that the seizures were not caused by the virus itself, but by the immune system's response to the infection. They said that something sets off a chain of events that begins with leakage of fluid from blood vessels into the meninges, the protective covering of the brain and spinal cord, followed by swelling, which in turn leads to seizures.

"T-cells, which are designed to attack the virus, were thought to be the bad guys, but no one understood the exact cellular dynamics involved in infection-induced seizures," Nature magazine quoted Dr. Kim, who did the intravital two-photon microscopic imaging in the study, as saying.

Upon noticing the behaviour of the T-cells, the researchers observed that rather than attacking cells infected with the virus, they wandered around, apparently unable to recognize their targets. "Up to a point, the T-cells did everything they should do. They made copies of themselves and migrated to where the virus was, but when they got there, they couldn't do the right thing. At least they didn't do what we expected them to, which was to stick tightly to the infected cells," Dr. Dustin said.

That observation provided the first clue that T-cells could not be causing fluid to leak from the blood vessels into the meninges, said the researchers. Another series of experiments showed that the real villains were monocytes and neutrophils, two types of white blood cells that usually fight bacteria, not viruses. With the aid of intravital microscopy, the researchers found that massive numbers of these white blood cells breaking through the walls of blood vessels into the meninges, opening the floodgates for fluid to pour out and cause swelling.

According to the researchers, unable to kill the virally infected cells, the T-cells appeared to be summoning monocytes and neutrophils to the site of infection, which turns out to be the wrong call. Although many questions remain, "we've discovered a totally new target-the neutrophils and monocytes recruited by the T-cells," Dr. Dustin says, "If you can prevent that recruitment process, either by inhibiting the T-cells or, preferably, inhibiting the monocytes and neutrophils, you can probably prevent the disease."

Source-ANISRM