From the WashU Newsroom…
More than 10,000 people in the United States are living with memory loss and other persistent neurological problems that occur after West Nile virus infects the brain.
Now, a new study in mice suggests that such ongoing neurological deficits may be due to unresolved inflammation that hinders the brain’s ability to repair damaged neurons and grow new ones. When the inflammation was reduced by treatment with an arthritis drug, the animals’ ability to learn and remember remained sharp after West Nile disease.
“These memory disturbances make it hard for people to hold down a job, to drive, to take care of all the duties of everyday life,” said senior author Robyn Klein, MD, PhD, a professor of medicine at Washington University School of Medicine in St. Louis. “We found that targeting the inflammation with the arthritis drug could prevent some of these problems with memory.”
The findings are available online in Nature Immunology.
Spread by the bite of a mosquito, West Nile virus can cause fever and sometimes life-threatening brain infections known as West Nile encephalitis. About half the people who survive the encephalitis are left with permanent neurological problems such as disabling fatigue, weakness, difficulty walking and memory loss. These problems not only persist but often worsen with time.
Klein and colleagues previously had shown that during West Nile encephalitis, the patient’s own immune system destroys parts of neurons, leading to memory problems.
“We started wondering why the damage isn’t repaired after the virus is cleared from the brain,” said Klein, vice provost and associate dean for graduate education for the Division of Biology & Biomedical Sciences. “We know that neurons are produced in the part of the brain involved in learning and memory, so why weren’t new neurons being made after West Nile infection?”
To find out, Klein; co-first authors Michael Vasek, a postdoc researcher, and graduate research assistant Charise Garber; and colleagues injected mice with West Nile virus or saltwater. During the acute infection, the mice received several doses of a chemical compound that tags neural cells as they are formed. Forty-five days after infection, the researchers isolated the tagged cells from the mice’s brains and assessed how many and what kinds of cells had been formed during the first week of infection.
Mice ill with West Nile disease produced fewer neurons and more astrocytes – a star-shaped neural cell – than uninfected mice. Astrocytes normally provide nutrition for neurons, but the ones formed during West Nile infection behaved like immune cells, churning out an inflammatory protein known as IL-1.
IL-1 is an indispensable part of the body’s immune system. It is produced by immune cells that swarm into the brain to fight invading viruses. Once the battle is won, the immune cells depart and IL-1 levels in the brain fall.
But in mice recovering from West Nile infection, astrocytes continue to produce IL-1 even after the virus is gone. Since IL-1 guides precursor cells down the path toward becoming astrocytes and away from developing into neurons, a vicious cycle emerges: Astrocytes produce IL-1, which leads to more astrocytes while also preventing new neurons from arising.
Hampered by an inability to grow new neurons, the brain fails to repair the neurological damage sustained during infection, the researchers said.
“It’s almost like the brain gets caught in a loop that keeps IL-1 levels high and prevents it from repairing itself,” said Klein, who is also a professor of neuroscience and of pathology and immunology.
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