How do meningitis bacteria invade the brain?

Bacteria can slip into the brain through cells lining the brain’s protective layers, a new study finds. The results hint at how the bacteria took hold of a deadly infection called meningitis.

In mice infected with meningitis-causing bacteria, the microbes exploit previously unknown communication between pain-causing nerve cells and immune cells to bypass the brain’s defenses, researchers report on March 1. nature. The results also suggest a new way to potentially delay the onset – using epilepsy drugs to disrupt cell conversations.

Bacterial meningitis is an infection of the protective layers, or meninges, of the brain that affects 2.5 million people globally each year. Severe and sometimes persistent headaches can cause neurological injury or death.

“Unexpectedly, pain fibers are actually hijacked by bacteria when they try to invade the brain,” says Isaac Chiu, an immunologist at the Harvard School of Public Health in Boston. Normally, pain can be expected to be a warning to us that the bacteria are being blocked in some way, he says. “We found the opposite…. This [pain] the signal is used by bacteria for advantage.’

It is known that sensory neurons and immune cells coexist in the meninges, especially in the outermost layer called the dura mater.SN: 11/11/20). So to see what role pain and immune cells play in bacterial meningitis, Chiu’s team infected mice with two bacteria known to cause infection in humans; Streptococcus pneumoniae and S. agalactiae. The researchers then observed where that bacteria was grown in mice that had been genetically engineered to lack pain-sensing nerve cells and compared those spots in mice with intact nerve cells.

Mice without nociceptive neurons had fewer bacteria in their meninges and brains than those with nerve cells, the team found. This is contrary to the belief that pain in meningitis serves as a warning signal to the immune body, prompting it to act.

Further tests have shown that the bacteria trigger a chain of events of the immune system, starting with the microbes secreting toxins in the hard mother.

Toxins bind to pain neurons, which in turn release a molecule called CGRP. This molecule is now known to bind to a receptor on immune cells, where it helps regulate the mother’s immune responses. Injecting the infected mice with more CGRP lowered the number of dural immune cells and helped fight the infection, the researchers found.

The team also took a closer look at the receptor that CGRP binds to. Mice infected without the receptor generated fewer bacteria in the brain. But in the burdens with the receptor, the immune cells that ingest the bacteria and the supplements are weakened.

The findings suggest that either blocking CGRP release or preventing it from binding to immune cells may help delay infection.

In humans, neuroscientists know that CGRP is a trigger for headache medication — it’s already a standard migraine medication (SN: 6/5/18). So the researchers gave five mice a migraine medication that blocks the effects of CGRP and infected them. S. pneumoniae. After infection, the medicated mice had less bacteria in their meninges and brains, took longer to show symptoms, and did not lose as much weight and live longer than the mice that were not given the medication.

The finding suggests that olcegepant may slow down the infection. Although the mice bought a few extra hours, it depends on the meningitis, which can develop in a very short time. In the same way, olcegepant was used in humans to give doctors time to treat meningitis. But the effect probably isn’t as dramatic in humans, says Michael Wilson, a neurologist at the University of California, San Francisco who was not involved with the work.

Scientists still need to determine whether pain-sensing cells and immune cells have the same relationship in the human dura mater, and whether epilepsy drugs could treat bacterial meningitis in humans.

Neurologist Avindra Nath is skeptical. Clinicians think the immune response and inflammation damage the brain in meningitis, says Nath, whose team researches infections of the nervous system at the National Institute of Neurological Disorders and Stroke in Bethesda, Md. Therefore, treatment involves drugs that suppress the immune response, rather than drugs that increase migraines.

Chiu acknowledges this but notes that there is room for both approaches. If the dural mother’s immune cells could prevent the head infection from jumping, the bacteria could penetrate some of the defenses, reducing brain inflammation.

This study may ultimately change how clinicians treat patients, Wilson says. But the first defense still shows something new about the brain.