A new study led by researchers at
Harvard Medical School details the step-by-step cascade that allows bacteria to
break through the brain's protective layers—the meninges—and cause brain
infection, or meningitis, a highly fatal disease.
The research, conducted in mice and
published March 1 in Nature, shows that bacteria exploit nerve cells in
the meninges to suppress the immune response and allow
infection to spread into the brain.
"We've identified a neuroimmune
axis at the protective borders of the brain that is hijacked by bacteria to
cause infection—a clever maneuver that ensures bacterial survival and leads to
widespread disease," said study senior author Isaac Chiu, associate professor
of immunology in the Blavatnik Institute at HMS.
The study identifies two central players
in this molecular chain of events that leads to infection—a chemical released
by nerve cells and an immune cell receptor blocked by the chemical. The study experiments
show that blocking either one can interrupt the cascade and thwart the
bacterial invasion.
If replicated through further research,
the new findings could lead to much-needed therapies for this hard-to-treat
condition that often leaves those who survive with serious neurologic damage.
Such treatments would target the
critical early steps of infection before bacteria can spread deep into the
brain.
"The meninges are the final tissue
barrier before pathogens enter the brain, so we have to focus our treatment
efforts on what happens at this border tissue," said study first author
Felipe Pinho-Ribeiro, a former post-doctoral researcher in the Chiu lab, now an
assistant professor at Washington University in St. Louis.
A recalcitrant disease
in need of new treatments
More than 1.2 million cases of
bacterial meningitis occur globally each year, according to the U.S. Centers
for Disease Control and Prevention. Untreated, it kills seven out of 10 people
who contract it. Treatment can reduce mortality to three in 10. However, among
those who survive, one in five experience serious consequences, including
hearing or vision loss, seizures, chronic headache, and other neurological
problems.
Current therapies—antibiotics that kill
bacteria and steroids that tame infection-related inflammation—can fail to ward
off the worst consequences of the disease, particularly if therapy is initiated
late due to delays in diagnosis. Inflammation-reducing steroids tend to
suppress immunity, weakening protection further and fueling infection spread.
Thus, physicians must strike a precarious balance: They must rein in
brain-damaging inflammation with steroids, while also ensuring that these immunosuppressive drugs do
not further disable the body's defenses.
The need for new treatments is magnified by the lack of a universal meningitis vaccine. Many types of bacteria can cause meningitis, and designing a vaccine for all possible pathogens is impractical. Current vaccines are formulated to protect against only some of the more common bacteria known to cause meningitis. Vaccination is recommended only for certain populations deemed at high risk for bacterial meningitis. Additionally, vaccine protection wanes after several years.
Scientists
have identified the maneuvers bacteria use to invade the brain and cause
meningitis. Shown here are pain receptors (in red) in the brain’s protective
layers, known as meninges. When activated by bacteria, pain receptors release a
chemical that disables the normal protective functions of immune cells known as
macrophages (in blue), weakening the brain’s defenses. Credit: Chiu Lab/Harvard
Medical School
Chiu and colleagues have long been
fascinated by the interplay between bacteria and the nervous and immune systems
and by how the crosstalk between nerve cells and immune cells may
either precipitate or ward off disease. Previous research led by Chiu has shown
that the interaction between neurons and immune cells plays a role in certain
types of pneumonia and in flesh-destroying bacterial infections.
This time around, Chiu and Pinho-Ribeiro
turned their attention to meningitis—another condition in which they suspected
the relationship between nervous and immune systems plays a role.
The meninges are three membranes that
lie atop one another, wrapping the brain and spinal cord to shield the central
nervous system from injury, damage, and infection. The outermost of the three
layers—called dura mater—contains pain neurons that detect signals. Such
signals could come in the form of mechanical pressure—blunt force from impact
or toxins that make their way into the central nervous system through the
bloodstream. The researchers focused precisely on this outermost layer as the
site of initial interaction between bacteria and protective border tissue.
Recent research has revealed that the
dura mater also harbors a wealth of immune cells, and that immune cells and
nerve cells reside right next to each other—a clue that captured Chiu's and
Pinho-Ribeiro's attention.
"When it comes to meningitis, most
of the research so far has focused on analyzing brain responses, but responses
in the meninges—the barrier tissue where infection begins—have remained
understudied," Ribeiro said.
What exactly happens in the meninges
when bacteria invade? How do they interact with the immune cells residing
there? These questions remain poorly understood, the researchers said.
How bacteria break
through the brain's protective layers
In this particular study, the
researchers focused on two pathogens—Streptococcus pneumoniae and Streptococcus
agalactiae, the leading causes of bacterial meningitis in humans. In a series
of experiments, the team found that when bacteria reach the meninges, the
pathogens trigger a chain of events that culminates in disseminated infection.
First, researchers found that bacteria
release a toxin that activates pain neurons in the meninges. The activation of
pain neurons by bacterial toxins, the researchers noted, could explain the severe,
intense headache that is a hallmark of meningitis. Next, the activated neurons
release a signaling chemical called CGRP. CGRP attaches to an immune-cell
receptor called RAMP1. RAMP1 is particularly abundant on the surface of immune
cells called macrophages.
Once the chemical engages the receptor,
the immune cell is effectively disabled. Under normal conditions, as soon as
macrophages detect the presence of bacteria, they spring into action to attack,
destroy, and engulf them. Macrophages also send distress signals to other
immune cells to provide a second line of defense. The team's experiments showed
that when CGRP gets released and attaches to the RAMP1 receptor on macrophages,
it prevented these immune cells from recruiting help from fellow immune cells.
As a result, the bacteria proliferated and caused widespread infection.
To confirm that the bacterially induced
activation of pain neurons was the critical first step in disabling the brain's
defenses, the researchers checked what would happen to infected mice lacking
pain neurons.
Mice without pain neurons developed less
severe brain infections when infected with two types of bacteria known to cause
meningitis. The meninges of these mice, the experiments showed, had high levels
of immune cells to combat the bacteria. By contrast, the meninges of mice with
intact pain neurons showed meager immune responses and far fewer activated
immune cells, demonstrating that neurons get hijacked by bacteria to subvert
immune protection.
To confirm that CGRP was, indeed, the
activating signal, researchers compared the levels of CGRP in meningeal tissue
from infected mice with intact pain neurons and meningeal tissue from mice
lacking pain neurons. The brain cells of mice lacking pain neurons had barely
detectable levels of CGRP and few signs of bacterial presence. By contrast,
meningeal cells of infected mice with intact pain neurons showed markedly
elevated levels of both CGRP and more bacteria.
In another experiment, the researchers
used a chemical to block the RAMP1 receptor, preventing it from communicating
with CGRP, the chemical released by activated pain neurons. The RAMP1 blocker
worked both as preventive treatment before infection and as a treatment once
infection had occurred.
Mice pretreated with RAMP1 blockers
showed reduced bacterial presence in the meninges. Likewise, mice that received
RAMP1 blockers several hours after infection and regularly thereafter had
milder symptoms and were more capable of clearing bacteria,
compared with untreated animals.
A path to new
treatments
The experiments suggest drugs that block
either CGRP or RAMP1 could allow immune cells to do their job properly and
increase the brain's border defenses.
Compounds that block CGRP and RAMP1 are
found in widely used drugs to treat migraine, a condition believed to originate
in the top meningeal layer, the dura mater. Could these compounds become the
basis for new medicines to treat meningitis? It's a question the researchers
say merits further investigation.
One line of future research could
examine whether CGRP and RAMP1 blockers could be used in conjunction with
antibiotics to treat meningitis and augment protection.
"Anything we find that could impact
treatment of meningitis during the earliest stages of infection before the
disease escalates and spreads could be helpful either to decrease mortality or
minimize the subsequent damage," Pinho-Ribeiro said.
More broadly, the direct physical
contact between immune cells and nerve cells in the meninges offers tantalizing
new avenues for research.
"There has to be an evolutionary
reason why macrophages and pain neurons reside so closely together," Chiu
said. "With our study, we've gleaned what happens in the setting of
bacterial infection, but beyond that, how do they interact during viral infection,
in the presence of tumor cells, or the setting of brain injury? These are all
important and fascinating future questions."
Chiu and Ribeiro are inventors on U.S. patent application 2021/0145937A1, "Methods and Compositions for Treating a Microbial Infection," which includes targeting CGRP and its receptors to treat infections.
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