Meningitis Bacteria Trigger Headaches, Then Sneak Into the Brain

Meningitis Bacteria Trigger Headaches, Then Sneak Into the Brain,Researchers find that bacteria stimulate a headache-causing pain pathway to suppress the immune system and infect the brain. 

Meningitis Bacteria Trigger Headaches, Then Sneak Into the Brain

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Bacterial meningitis is a disease characterized by an infection of the meninges—the delicate membranes that envelop and protect the brain—which can cause life-threatening inflammation or stroke. Although rare, it’s lethal in 30 percent of patients, meaning therapies are sorely needed.

Now, a study published March 1 in Nature teases out how bacteria storm through the meninges and into the brain: by exploiting pain-sensing nerve cells to suppress the immune response. Armed with new insight into how the bacteria make their way to the brain, researchers may be able to develop better strategies for blocking infection, experts tell The Scientist.

“The study is very, very well done,” says Dorian McGavern, an immunologist at the National Institutes of Health (NIH) who was not involved in the study but wrote an accompanying perspective piece in Nature. “There’s a lot of mechanistic depth and some relevant findings to human disease.”

In his previous work in the skin and gut, study coauthor and Harvard Medical School immunologist Isaac Chiu had already established that pain-sensing neurons can alter immune responses after infection. “Nerve cells talk to immune cells,” Chiu tells The Scientist. Indeed, neurons are among the first cells to trigger an inflammatory response to harmful stimuli, a phenomenon known as neurogenic inflammation.

Pain is also a hallmark of meningitis, thanks to bundles of pain-sensing neurons that branch throughout the meninges. Their activation is thought to be the cause of the headaches often associated with bacterial meningitis, as well as of headaches generally.

Knowing that there’s crosstalk between neurons and immune cells in other tissues, Chiu wanted to “understand the role pain plays in meningitis,” he says. “Is it affecting the outcome of meningitis? Is it just a symptom?”

In the study, led by Felipe Pinho-Ribeiro, a former postdoc in the Chiu lab who is now an immunologist at Washington University in St. Louis, scientists injected mice with bacteria known to cause meningitis: Steptococcus pneumoniae and Steptococcus agalactiae. Within a few hours, the bacteria traveled to the outer membrane of the meninges, called the dura. Within a day, the bacteria had infiltrated the mice’s brains.

To tease out the role pain fibers play in bacterial meningitis, the team used a genetic engineering approach to create mice without pain neurons. They found that, in the hours after infection, these mice fought infection more effectively than normal mice. Although the mice eventually succumbed to the infection, the researchers found fewer bacteria and larger numbers of immune cells, mainly infection-fighting neutrophils and monocytes, in their dura.

This suggested that, during infection, pain fibers suppress immune cells at the dura, which Chiu calls “a key barrier site.”

But that still left Chiu wondering how neurons might be suppressing immune cells. He knew from the literature that when activated, pain-sensing neurons release CGRP, a molecule implicated in migraines. CGRP attaches to the RAMP1 receptor, which is found on immune cells such as macrophages. So, Chiu hypothesized that CGRP might be mediating the communication between neurons and immune cells.

To test this theory, first, the team used calcium imaging in vitro to show that the meningitis-causing bacteria activate neurons, causing them to release CGRP.

Then the team went on to target the CGRP receptor RAMP1. Chiu and his team injected mice with a drug that blocked RAMP1 before infecting them with the bacteria. A few hours after infection, the animals that had received the drug had fewer bacteria in their meninges and showed a stronger immune response in the dura than animals that hadn’t received the drug.

Together, the findings suggest that CGRP is responsible for immune suppression during bacterial meningitis. “The bacteria can suppress the immune system by hijacking it,” says Chiu.

Questions remain about why CGRP suppresses immune cells in the dura in the first place, and why a mechanism exists that bacteria can exploit to better infect the brain.

“Biology is always full of surprises,” says Chiu. “I think we underestimate microbes. They have very clever ways that they’ve evolved to survive inside of us.

Chiu says that those are questions for the future, but he suspects that the system exists so that inflammation doesn’t get out of control near the brain and cause damage, and that bacteria have just evolved a way to take advantage of an otherwise protective mechanism. “Inflammation is a double-edged sword,” says Chiu. “You need to fight bacteria but there could be tissue damage . . . if it goes too far.”

According to Chiu, there could be important clinical implications of the findings. Because CGRP blockers are already clinically available and safe to use in humans, “it’s exciting to be able to think about applying [CGRP blockers] in the case of acute bacterial meningitis,” he says. Chiu is on the scientific advisory board for GlaxoSmithKline, which markets the CGRP-blocking migraine drug sumatriptan as Imitrex. However, Chiu says that he doubts that CGRP antagonists alone could be used to treat meningitis, given that mice still eventually die from the infection.

McGavern agrees that, while there are therapeutic implications of the findings, it might be a bit challenging to apply them to treatment directly because blocking pain only attenuated disease and didn’t eliminate it. “But it might be a way to try to modulate immunity” before the disease takes hold.