Inflammation is culprit behind long COVID, study suggests

Dr. William Banks had a case of COVID-19 that carried some hallmarks of long COVID, a debilitating version of the virus that lingers for months and raises risk of long-term impairment.

“I couldn't remember things and I lost my ambition to remember,” Banks said. “The two together were terrible.”

Banks, Shelly Erickson and a team of researchers with the University of Washington School of Medicine, the Veterans Affairs Puget Sound Health Care System, and Oregon Health & Science University have shed light on the likely culprit of symptoms like foggy brain and vanishing memory: inflammation.

Their conclusions were published recently in the journal Brain, Behavior, and Immunity. The findings add a major piece to the puzzle of how COVID-19, a lung disease, becomes long COVID, a disease of the brain.

In the mouse study, the S1 protein, attached to all SARS-CoV-2 variants of concern, readily passed through the blood-brain barrier, they found. Once there, the protein caused inflammation that Banks says can spur problems with learning and memory and accelerate the effects of Alzheimer’s and other cognitive impairments.

“SARS-CoV-2 causes inflammation in the brain. That’s the critical point,” said Banks, a professor with the UW Division of Gerontology & Geriatric Medicine and associate chief of staff for Research and Development at the VA Puget Sound Health Care System. “Basically, the S1 protein, either by itself or as part of the virus, gets into the brain and you’re off to the races.”

In the study, the researchers used two noninfective models of the virus, which both entered the mouse brains easily. The S1 protein is the structure that looks like a little red flower in the most common illustrations of the novel coronavirus. It is the viral attachment protein and determines where the virus goes. Researchers also showed that the virus model could not cross the blood-brain barrier without the S1 protein. Of the five COVID variants, Omicron passed the barrier most easily.

They also found the S1 protein can be blocked from the brain by targeted antibodies. This, Banks said, is another reason to get vaccinated, since the vaccine rapidly produces antibodies against S1, preventing it from entering the brain.

People with Alzheimer’s and other cognitive diseases seem to be at particular risk when the S1 protein crosses into the brain.

“It may make it worse, bring it on sooner, or it may cause its own version of cognitive impairment,” Banks said. “By analogy, that's what diabetes does: It increases the risk of Alzheimer's disease and it also creates its own version of cognitive impairment. This sort of ups the odds that something like this could happen with SARS-CoV-2.”

Banks said next steps for study include examining animals to see what the long-term effects of inflammation are on an brain that’s been infected with COVID-19 for longer periods. Months translate to years in the brains of mice, for instance, allowing a more advanced understanding of the disease. The researchers also want to test candidate drugs that might block or prevent certain kinds of neuroinflammation.

Finding a source of brain inflammation amid the quickly advancing understanding of mechanisms for dementia diseases raises an alarm, Banks said.

“I think the other big concern is that we're showing that the Alzheimer's disease model has a lot more inflammation, so the study is really kind of advancing all the things that we had feared,” Banks said. “But on the other hand, if it's true that brain inflammation is the culprit, which we also think is the culprit for cognitive impairment and brain injury in football injuries and everything else, then we're a little bit closer to figuring out what needs to be studied.”

Written by Chris Talbott - 206-543-7129, talbottc@uw.edu

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