More than half of the survivors of West Nile virus brain infections are left with memory disorders that make everyday tasks such as remembering the route from home to work challenging. Similar issues can arise in the aftermath of other viral infections, such as the “brain fog” that plagues some people after a diagnosis of COVID-19. These memory problems can persist for months or years — in some cases even worsening over time — and doctors have no good way to prevent or treat them.
Robyn S. Klein, MD, PhD, the Robert E. and Louise F. Dunn Distinguished Professor of Medical Sciences at Washington University School of Medicine in St. Louis, has received an $8.7 million grant to study how viruses may cause diseases of “pathological forgetting.” The grant, from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH), is a research program award designed to provide stable, long-term funding so an investigator can tackle thorny scientific problems. Klein plans to use the funding to investigate why emerging viral infections sometimes trigger memory problems that persist long after a virus has been cleared from the body.
“Forgetfulness is normal,” said Klein, who directs the Center for Neuroimmunology & Neuroinfectious Diseases at the School of Medicine. “You can’t remember everything. You don’t want to. Excessive remembering can interfere with forming new short-term memories. There’s a normal process of removing and refining connections between neurons to allow for normal forgetting and, after some viral infections, this process somehow gets revved up and creates pathological forgetting.”
The process may be mediated by the immune response to infection. Viruses such as West Nile that infect the brain directly are most likely to trigger memory disorders, but even viruses that never enter the brain, such as the one that causes COVID-19, can lead to cognitive problems. Klein suspects that some viral infections trigger the release of immune molecules that inappropriately activate immune or other cells, which then injure neurons or destroy some of the connections between them. This activation may not resolve when the virus is cleared, leading to ongoing brain damage and worsening memory problems.
“It’s unclear whether the tendency to cause memory disorders is a feature of particular viruses or whether it’s the result of more general immune and inflammatory responses that could be triggered by any number of different viruses,” Klein said. “I think there has not been enough attention in the neurodegenerative field on neuroimmune mechanisms that may contribute to dementias. Viral infections can trigger neurodegenerative processes that continue and worsen for years after the virus is cleared, without the virus ever entering the central nervous system. So if someone develops dementia, it may be the result of an abnormal recovery process from a past infection.”
Klein, who is also a professor of medicine, of pathology & immunology and of neuroscience, aims to identify the molecules and cells involved in memory dysfunction as a step toward finding treatments for infection-induced pathological forgetting. Part of the project will be a collaboration with imaging scientists to develop biomarkers to follow inflammation in the brain of infected animals and correlate it with the development of memory disorders.