Traumatic brain injury and other injuries to blood vessels in
the brain, like stroke, are a leading cause of long-term disability or
death. Researchers at the National Institute of Neurological Disorders
and Stroke (NINDS), part of the National Institutes of Health, have
found a possible explanation for why some patients recover much more
poorly from brain injury if they later become infected. The findings
were published in Nature Immunology.
Making use of a mouse model for mild traumatic brain injury (mTBI) that they had developed previously, the team of researchers led
by NINDS scientist Dorian McGavern PhD, discovered that viral,
fungal, or a mimic for bacterial infections all impacted blood vessel
repair within the meninges, the protective covering of the brain. When
they looked closer, they observed that some cells of the immune system
no longer moved into the site of the injury, which occurred in the
uninfected animals, suggesting they were responding to systemic
infection. The study also looked in a second injury model affecting the
blood vessels in the brain, called a cerebrovascular injury, and
saw a similar effect on repair.
“Evolution prioritizes mobilizing the immune system to fight off
infection over repair,” said Dr. McGavern. “Because the body is dealing
with a greater threat, cells that would normally repair the damaged
blood vessels in or around the brain are needed elsewhere.”
This change in priority for the immune system is not permanent, as
infected mice were able to eventually repair the blood vessel damage at a
later time compared to uninfected mice, unless a second infection was
encountered. This timing is especially critical in the case of mice with cerebrovascular injury,
because the delay in response produced by infection led to permanent
cognitive dysfunction and damage to the brain tissue. The repaired brain
blood vessels, which are normally very well sealed, remained
“The presence of infection causes the immune system to take a break
from repair while it fights off the virus,” said Dr. McGavern. “In the
case of mild traumatic brain injury, this seems to be ok, but when you have a large
vascular injury in the brain itself, like a stroke, every minute counts.
These findings highlight the utmost importance in quickly identifying
and treating infections in patients.”
Although the presence of infection was affecting the immune system’s
ability to respond to mild traumatic brain injury, the exact cause remained unknown. When cells
in the body become infected, they call for help by releasing proteins
that signal the immune system. One group of proteins released after
viral infection are called type I interferons (IFN-I), which turn on a
variety of genes that affect the immune response. Following mild traumatic brain injury, the
researchers saw a large increase in IFN-I-related genes in infected
compared to non-infected mice.
Additional experiments confirmed the importance of IFN-I in shifting
the focus of the immune system away from blood vessel repair. Mice that
have had their genome altered so that their immune cells cannot sense
the presence of IFN-1 showed similar rates of repair after mild traumatic brain injury regardless of whether they had a viral infection. Deleting the IFN-I
sensor only in one type of immune cell known to be important
for repairing blood vessels after mild traumatic brain injury also eliminated the defect
produced by infection. Finally, directly applying one of the IFN-I
proteins directly to the injury site prevented blood vessel repair
without the presence of infection. IFN-I signaling also appeared to play
a critical role in the repair delay seen in mice with cerebrovascular injury.
Systemic infections are common among patients hospitalized for traumatic brain injury and cerebrovascular injury, and they have been linked to poorer outcomes. The findings in
this study highlight the importance of controlling those infections
(whether bacterial or viral) as quickly as possible. This is especially
true for patients with cerebrovascular injury, as a delay in repair can lead to permanent damage
to the brain.
This study was supported by the Intramural Research Program at NINDS.
the nation’s leading funder of research on the brain and nervous
system. The mission of NINDS is to seek fundamental knowledge about the
brain and nervous system and to use that knowledge to reduce the burden
of neurological disease.
Source: News Release
September 23, 2021