SARS-CoV-2 spike protein mutation identified as key to brain infection

Researchers at Northwestern University and the University of Illinois-Chicago have identified a specific mutation in the coronavirus spike protein that appears to be the key to how SARS-CoV-2 breaches the blood-brain barrier and infects the central nervous system. The finding, published in Nature Microbiology in August 2024, offers a potential explanation for why some COVID-19 patients experience persistent neurological symptoms—and hints at how scientists might one day develop treatments to prevent or clear the virus from brain tissue.

The discovery emerged from a straightforward but revealing experiment. Researchers infected mice with SARS-CoV-2 and then sequenced the viral genomes recovered from two different sites: the lungs and the brain. What they found was striking. In the lungs, the spike protein—the outer structure that allows the virus to enter cells—remained largely unchanged from the original virus used in the infection. But in the brain, something different had happened. Most of the viruses that had successfully infected brain tissue carried a deletion, a missing piece, in a critical region of the spike protein that normally controls how the virus enters cells.

When the researchers took viruses carrying this deletion and introduced them directly into mouse brains, the mutation largely reversed itself when the virus traveled back to the lungs. This suggested the deletion was not a random accident but rather an adaptation—a change that made the virus better suited to infecting brain cells, even though it made it worse at infecting lung cells. "In order for the virus to traffic from the lung to the brain, it required changes in the spike protein that are already known to dictate how the virus gets into different types of cells," explained Judd Hultquist, an assistant professor of medicine at Northwestern's Feinberg School of Medicine and one of the study's lead authors. "We think this region of spike is a critical regulator of whether or not the virus gets into the brain."

The implications reach directly into the lived experience of millions of COVID-19 patients. The virus has long been associated with a constellation of neurological symptoms: loss of smell and taste, cognitive difficulties sometimes called "brain fog," and the broader syndrome known as long COVID. Until now, scientists have not been certain whether these symptoms result from the virus directly infecting brain cells or from some lingering immune response that persists after the acute infection has passed. If the former is true—if long COVID is indeed caused by viral infection of the central nervous system—then understanding exactly how the virus gains entry to the brain becomes medically urgent.

"If it is caused by infection of cells in the central nervous system, our study suggests there may be specific treatments that could work better than others in clearing the virus from this compartment," Hultquist said. The research opens a door that has remained closed: the possibility of designing therapies that target not the virus in general, but specifically the virus as it exists in the brain, using knowledge of this spike protein mutation as a guide.

The study was supported by multiple federal agencies, including the National Institutes of Health and the Department of Defense, reflecting the significance researchers place on understanding how SARS-CoV-2 behaves in the nervous system. The work involved five additional researchers from Northwestern, each contributing to the genomic analysis and viral evolution studies that made the discovery possible. What began as an unexpected finding—that viruses in the brain carried a different genetic signature than viruses in the lungs—has become a potential roadmap for treating one of the pandemic's most persistent and least understood complications.