A new study shows that bacteria can enter the brain by capturing cells in the brain’s protective layers. The findings hint at how a deadly infection called bacterial meningitis spreads.
In mice infected with bacteria that cause meningitis, the microbes use a previously unknown connection between pain-sensing nerve cells and immune cells to get past the brain’s defenses, researchers report March 1 in Nature . The findings also hint at a new way to possibly delay the invasion — using migraine drugs to interrupt these conversations between cells.
Bacterial meningitis is an infection of the protective layers or meninges of the brain that affects 2.5 million people worldwide each year. This can cause severe headaches and sometimes permanent neurological damage or death.
“Unexpectedly, the bacteria take over the pain fibers as they try to invade the brain,” says Isaac Chiu, an immunologist at Harvard Medical School in Boston. Generally, you would expect pain to be a warning system for us to somehow shut down the bacteria, he says. “We found the opposite… This one [больовий] the signal is used by the bacteria to gain an advantage.”
Pain-sensing neurons and immune cells are known to coexist in the meninges, especially in the outer layer called the dura mater. 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 these bacteria settled in mice genetically engineered to lack pain-sensing nerve cells, and compared these resting sites to those found in mice with intact nerve cells.
The team found that mice without pain-sensing neurons had fewer bacteria in their meninges and brains than mice with nerve cells. This contradicts the idea that meningitis pain serves as a warning signal to the body’s immune system, mobilizing it into action.
Further tests showed that the bacteria triggered a chain of immune-suppressing events, starting with the microbes releasing toxins into the dura mater.
The toxins latched onto the pain neurons, which in turn released a molecule called CGRP. It is already known that this molecule binds to a receptor on immune cells, where it helps control the immune response of the dura mater. The researchers found that injecting infected mice with more CGRP reduced the number of dural immune cells and promoted the development of the infection.
The team also took a closer look at the receptor that CGRP binds to. In infected mice bred without the receptor, fewer bacteria entered the brain. But in those with the receptor, the immune cells that would otherwise engulf the bacteria and recruit reinforcements were turned off.
The findings suggest that preventing the release of CGRP or preventing it from binding to immune cells may help delay infection.
Neuroscientists know that CGRP is the driver of headaches—it’s already a target of migraine medications. So the researchers gave five mice the migraine drug olcegepant, which blocks the action of CGRP, and infected them S. pneumoniae . After infection, mice that were given the drug had less bacteria in their meninges and brains, took longer to develop symptoms, didn’t lose as much weight, and lived longer than mice that weren’t given the drug.
The finding suggests that olcegepant slowed down the infection. Although this only bought the mice a few extra hours, it is crucial for meningitis, which can develop just as quickly. If olcegepant worked the same way in humans, it could give doctors more time to treat meningitis. But the effect is probably not as dramatic in humans, warns Michael Wilson, a neuroscientist at the University of California, San Francisco, who was not involved in the work.
Scientists have yet to determine whether pain-sensing nerve cells and immune cells share the same interactions in the human dura mater, and whether migraine medications can help treat bacterial meningitis in humans.
Neurologist Avindra Nath has his doubts. Clinicians believe that the immune response and inflammation damage the brain during meningitis, says Nath, who heads the Nervous System Infections Research Group at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. Therefore, treatment involves the use of drugs that suppress the immune response, rather than enhance it, as migraine medications can do.
Chiu acknowledges this, but notes that there can be room for both approaches. If immune cells in the dura mater can prevent infection in the passageway, it may prevent some bacteria from getting through the defenses, minimizing brain inflammation.
This research may not ultimately change how clinicians treat patients, Wilson says. But it does reveal something new about one of the brain’s first lines of defense.
