COVID virus evolves more rapidly in the central nervous system than in the lungs, study finds

The coronavirus responsible for the COVID-19 pandemic evolves more rapidly in the brain than in the lungs, according to new research from University of Illinois Chicago and Northwestern University.

New viral variants created in the brain and other parts of the nervous system could also travel back to the lungs, where they could become transmissible, the researchers report in Nature Microbiology. That could spread new, dangerous variants of the virus.

"Potentially, this could be a source of novel variants of concern," said Justin Richner, assistant professor of microbiology and immunology at UIC and co-lead author of the paper. "It could be that the virus is using these different tissue sites to evolve new mutations, and then those can traffic back into the respiratory tract and spread throughout the population."

The study, conducted in mice, first tested how COVID-19 vaccination affects the mutation of viruses in the body. Five days after infection, researchers measured the number of viral variants present in different parts of the body. They were surprised to find more viral variation in the brain than in the lungs in both vaccinated and unvaccinated mice.

"The vaccination status didn't really determine the virus evolution, but we observed differences in the virus sequence in the brain versus the lung," Richner said. "That really set us on a totally unexpected trajectory."

Most mutations were in the gene for the viral spike protein, which the virus uses to enter and infect cells. Most changes were found in a region of the spike protein called the furin cleavage site.

"This site is of high interest because it is linked to the outbreak and transmissibility of the SARS-CoV-2 virus," Richner said. "It leads to more enhanced transmission of the virus and why it was able to much more easily transmit through the entire population."

However, most variants found in the brain disrupted the function of this spike protein site, producing strains that were less virulent when tested in subsequent experiments. The researchers hypothesized that the virus uses an alternative mechanism to infect cells in the central nervous system, driving the mutation of the new variants.

Despite the reduced virulence, researchers were alarmed by the ability of these viral variants to migrate from the central nervous system back to the lungs, where they could then potentially spread through the air to other individuals. The ability of the virus to rapidly evolve in immune-protected areas of the body, such as the brain or the testes, could drive future dangerous variants.

That possibility underscores the importance of vaccination, Richner said.

"This finding suggests that the vaccines are still important because the only way the virus reaches these distal tissues is if it establishes an infection and is able to replicate in the body," Richner said. "The vaccines are important to prevent the virus from reaching some of those distal tissues and undergo diversification."

In future work, the researchers hope to study how viruses travel from the central nervous system back to the lungs. They will also investigate potential links between the viral variants found in the brain and the neurological symptoms, such as "brain fog" and memory loss, associated with both acute and long COVID.

The collaboration between Richner's group and the research team of Judd Hultquist at Northwestern University highlights the close partnerships between Chicago research institutions established in the early days of the COVID-19 pandemic.

"I think that this research really speaks to the strength of the Chicago virology community," Richner said. "It was a truly collaborative project that would not be possible without both parties."

In addition to Richner, UIC co-authors on the paper include Jacob Class, Jazmin Galván Achi, Laura Cooper, Sarah Lutz and Lijun Rong.