Meningitis, a highly fatal illness, is caused by bacteria that break through the brain's protective layers. When blocked, the immune cell receptor can interrupt the cascade and prevent bacterial invasion. These findings may be applied to other disorders as well as in the early stages of infection.
Meningitis is caused by bacteria hijacking nerve- immune interactions, according to a research.
Researchers from Harvard Medical School have developed a step-by-step guideline that allows bacteria to break through the brain's protective layers — the meninges — and cause brain infection, or meningitis, a highly fatal illness.
The research, which was conducted in mice, was published recently in the journal Nature. Bacteria exploit nerve cells in the meninges to suppress the immune response and spread the infection into the brain.
"We've identified a neuroimmune axis at the protective edges of the brain that is hijacked by bacteria to cause infection," said study senior author Isaac Chiu, an associate professor of immunology at HMS.
Researchers have identified the methods bacteria use to invade the brain and cause meningitis. Meninges are shown here, along with a pain receptor (in red) in the brain's protective layers, which release a chemical that disrupts immune cells' normal protective functions (in blue), weakening the brain's defenses.
The research identifies two key players in the evolutionary chain of events that leads to infection, a chemical released by nerve cells and an immune cell receptor blocked by the chemical. Both parties are believed to be effective in thwarting the bacterial invasion.
If further study is followed, the new findings might lead to much-needed therapies for this difficult-to-treat illness that often leaves survivors with serious neurologic damage.
Solved therapies would focus on the very first steps of infection before bacteria spread deep into the brain.
"We must concentrate our treatment efforts on what happens at this border tissue," said study first author Felipe Pinho-Ribeiro, a former post-docoral researcher at Washington University in St. Louis.
According to the US Centers for Disease Control and Prevention, bacterial meningitis affects more than 1.2 million people every year in the world. If left untreated, it kills seven out of every ten people who contract it. Treatment can reduce mortality to three in 10, but one out of every five suffers severe neurological problems such as hearing or vision loss, chronic headache, and other neurological illnesses.
If therapy is initiated too late due to delays in diagnosis, current therapies may fail to eliminate the worst effects of the disease. This requires physicians to maintain a delicate balance: They must control brain damage as well as prevent infection spreading.
The absence of a universal meningitis vaccination is proving too restrictive. Current vaccinations are designed to protect only a few of the most common bacteria known to cause meningitis. Vaccination is recommended only for individuals who are at high risk for bacterial meningitis after a few years.
Chiu and his colleagues have long been interested in the relationship between bacteria and the nervous and immune systems, and in how the interaction between nerve cells and immune cells may either precipitate or ward off illness.
Chiu and Pinho-Ribeiro focused on meningitis, another condition in which they suspected a connection between the nervous and immune systems.
Meninges are three membranes that meet atop each other, encasing the brain and spinal cord in order to protect the central nervous system from injury, damage, and infection. Pain neurons that detect signals may be caused by mechanical pressure or contaminants that enter the central nervous system through the bloodstream.
Recent study has revealed that the dura mater also houses a large amount of immune cells, and that immune cells and nerve cells reside right next to each other — a clue that caught Chiu's and Pinho-Ribeiro's attention.
"The majority of research so far on meningitis has focused on brain responses, but responses in the meninges, the barrier tissue where infection begins, have remained unstudied," Ribeiro said.
When bacteria invades the meninges, what do they do? How do they interact with the immune cells that live there? These are still unknown, according to the researchers.
The researchers examined two pathogens, Streptococcus pneumoniae and Streptococcus agalactiae, which are the main culprits for human bacterial meningitis. In a series of experiments, the researchers discovered that when bacteria enter the meninges, the pathogens trigger a chain of events that culminates in disseminated infection.
Researchers discovered that bacteria releases a neurotoxic compound that activates pain neurons in the meninges. Next, the activated neurons release a signaling chemical called CGRP. RAMP1 is particularly abundant on immune cells called macrophages.
The immune cell is effectively disabled as CGRP is released and attached to the RAMP1 receptor on macrophages, preventing them from gaining access to other immune cells. The bacteria then spread and spread.
The researchers investigated what would happen to infected mice lacking pain neurons.
When exposed to two different types of bacteria known to cause meningitis, mice without pain neurons developed less severe brain infections. The meninges of these mice, the experiments demonstrated, had high immune responses but little activity, indicating that bacteria hijacks neurons to subvert immune protection.
Researchers examined meningeal tissue from infected mice with intact pain neurons to see if CGRP was indeed the activating signal. Both groups showed little evidence of bacterial presence in the meningeal cells.
The researchers also used a chemical to deactivate the RAMP1 receptor, thus blocking its ability to communicate with CGRP, the active pain hormone, in another experiment.
Mice who received RAMP1 blockers several hours after infection and frequently thereafter had milder symptoms and were more capable of clearing bacteria than untreated animals.
According to the investigations, medicines that block CGRP or RAMP1 might allow immune cells to perform their jobs correctly and strengthen the brain's border defenses.
Researchers say the presence of compounds that block CGRP and RAMP1 is evident in widely used medications to treat migraine, which is thought to originate in the top meningeal layer, the dura mater.
Future research may look at whether CGRP and RAMP1 blockers might be utilized alongside antibiotics to treat meningitis and enhance protection.
"Anything we discover that might improve the management of meningitis during the early stages of infection before it escalates and spreads might be useful either to reduce mortality or minimize the damage that follows," said Pinho-Ribeiro.
In terms of research, the direct physical contact between immune cells and nerve cells in the meninges opens up intriguing new possibilities.
“We’ve discovered what occurs in the context of viral infection, in the presence of tumor cells, or the setting of brain injury,” Chiu said.
Felipe A. Pinho-Ribeiro, Liwen Deng, Ozge Erdogan, Himanish Basu, Daping Yang, Simone Carneiro-Nascimento, Kathleen He, Glendon Wu, Beth Stevens, Kelly S. Doran, Dan Levy, and Isaac M. Chiu, 1 March 2023, Nature. DOI: 10.1038/s41586-023-05753-x
Liwen Deng, Dylan Neel, Himanish Basu, Daping Yang, Kathleen He, Alec Walker, Glendon Wu, and Beth Stevens of Harvard Medical School were co-authors, as well as Ozge Erdogan of the Harvard School of Dental Medicine; Kelly Doran of the University of Colorado; and Dan Levy and Simone Carneiro-Nascimento of Beth Israel Deaconess Medical Center.
The Burroughs Wellcome Foundation, the Kenneth Rainin Foundation, the Food Allergy Science Initiative and the Fairbairn Lyme Initiative all contributed to this work, as well as the Harvard Medical School Immunology Undergraduate Summer Program.
Chiu and Ribeiro are the inventors of US patent application 2021/0145937A1, "Methods and Compositions for Treating a Microbial Infection," which includes a focus on CGRP and its receptors in order to treat infections. Abbvie/Allergan and Moderna, Inc.
