Malaria is a parasitic infection that is spread by mosquitoes,
primarily in the developing world. According to the Centers for Disease
Control and Prevention, in 2015, there were more than 200 million cases
of malaria worldwide and 400,000 deaths from the disease, mainly in
children under five years old.
Although many people experience mild
symptoms, in some individuals the parasite affects the brain and causes
cerebral malaria, which kills 15 to 30% of patients with that
form of the disease. Individuals who survive cerebral malaria often
experience long-term neurological symptoms including cognitive
impairment and limb paralysis.
‘By looking into the living brain, scientists were able to watch the chain of events that cause cerebral malaria. The findings also suggest that there may be a simple treatment available to stop this deadly disease.’
The cause of death from cerebral malaria
is often due to brain swelling and bleeding, but the mechanisms leading
to these outcomes are not completely understood.
Using state-of-the-art brain imaging technology, scientists at the
National Institutes of Health filmed what happens in the brains of mice
that developed cerebral malaria (CM). The results, published in PLOS Pathogens
, reveal the processes that lead to fatal outcomes of the disease and suggest an antibody therapy that may treat it.
"By looking into the living brain, we were able to watch the chain
of events that cause cerebral malaria to kill thousands of people every
year," said Dorian McGavern, scientist at the NIH's National
Institute of Neurological Disorders and Stroke (NINDS). "Our study also
suggests there may be a simple treatment available to stop this deadly
Previous studies in the rodent model of this disease indicated CD8+ T
cells played a key role in the development of CM so Dr. McGavern's team
focused its cameras on those cells.
Dr. McGavern and his colleagues peered inside the brains of mice
infected with a parasite that causes CM, using an imaging technology
known as intravital microscopy, which allowed them to watch cells in
The findings of this study showed that as red blood cells containing
the parasite adhere to cerebral blood vessels (a hallmark of CM), the
immune system attempts to clean them off. Despite these efforts,
endothelial cells making up the walls of cerebral blood vessels shed
bits of the parasite, which CD8+ T cells recognize, causing those immune
cells to attach to and attack the vessels. Once the CD8+ T cells
amassed on the surface of brain blood vessels, the vessels began to
leak. The subsequent leaking led to swelling and increased pressure in
the brain, which was fatal. Results also showed that the CD8+ T cells
preferentially interacted with blood vessels in the brain and not in
other parts of the body.
To determine which parts of the brain were affected by these events,
the researchers injected mice with dyes that marked dead cells and
blood vessel leakage. The results indicated that the brain regions with
the most damaged vessels and cell death were the olfactory bulb (the
area involved in sensing smell) and crucially, the brainstem, an area
that controls such vital functions as breathing and heart rate.
In another set of experiments, Dr. McGavern's group tested a
potential therapy to see if it could be used to remove the CD8+ T cells
from vessel walls. Initially, they watched as CD8+ T cells began to
interact with the cerebral blood vessels in the CM mice. Then, they
treated the mice with two FDA-approved, intravenous drugs that block the
molecules that CD8+ T cells use to attach to blood vessels. Within 30
minutes of the treatment, the CD8+ T cells broke off from the blood
vessels and could not stick to them, preventing the fatal brain swelling
in all of the treated mice. These findings suggest that the
interactions between CD8+ T cells and blood vessels lead to death from
CM and preventing that binding may increase survival from the disease.
"These movies show us a terrible side effect sometimes associated
with malaria - the parasite can fool the body's immune system into
attacking the blood vessels within its own brain," said Dr. McGavern.
In future studies, Dr. McGavern and his colleagues will examine how
the interaction between CD8+ T cells and cerebral vessels causes blood
leakage and ways in which the brain recovers from CM infection. In
addition, the live-action imaging technology from in this study may be
used to watch ways in which other mosquito-borne illnesses, such as Zika
and dengue, affect the brain.