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Measles Virus Mutations Found to Drive Rare Lethal Brain Infection

Measles virus

NEW YORK – A team from the Mayo Clinic in Rochester, Minnesota, and other centers in the US has used genome sequencing to dig into the spatial dynamics of a rare form of measles virus infection that affects the brain, leading to potentially deadly complications that can arise up to a decade after an acute infection.

The condition, known as subacute sclerosing panencephalitis (SSPE), represents a form of brain tropism found in roughly one in every 10,000 measles cases. As part of it, investigators suspected that "infectious units" made up of genomically diverse viruses move into the brain.

"Although vaccination against measles prevents SSPE, this lethal disease is resurging due to vaccine hesitancy and missed immunizations due to COVID-19 related disruptions," senior and co-corresponding author Roberto Cattaneo, a researcher affiliated with the Mayo Clinic and the Mayo Clinic Graduate School of Biomedical Sciences, wrote in PLOS Pathogens on Thursday.

The researchers attempted to understand measles virus evolution and spread in SSPE in more detail by sequencing viral genomic RNA from frozen brain autopsy samples from a 24-year-old SSPE patient who was born in Central America and resided in the US. The man's brain had been donated to the US Centers for Disease Control and Prevention after his death from SSPE.

By sequencing the virus in more than a dozen spatially defined areas of the donated brain to an average depth of 890,000-fold coverage, the researchers were able to retrace its spread to and within the brain.

"Our study is based on 15 specimens from different brain regions, and the viral genome is covered almost a million times," Cattaneo said in an email. "This allowed us to reconstruct the evolutionary history of the spread of this virus, and, to our knowledge, of any virus, in the human brain for the first time."

Their results suggested that measles virus genomes become increasingly mutated as they move into other parts of the brain from the frontal cortex, where the individual's SSPE infection appeared to initially take hold in the brain.

The analyses also pointed to the presence of at least two viral subpopulations that co-occurred in the brain.

"We discovered that brain colonization was driven by multiple distinct genome lineages that co-replicated even at the level of single cells," the authors reported, adding that adaptation to the brain "yielded a genetically diverse and widely dispersed viral genome population at patient death."

Digging into mutations present in each subpopulation provided a look at the alterations advantageous to the virus in the brain's environment, setting them against the types of mutations found in past studies on smaller brain autopsy sample sets.

"Previous studies were extremely useful to interpret our data," Cattaneo noted, "because they identified classes of mutations that seemed important for virus adaptation to the brain, and sometimes brought formal proof of the importance of these mutations."

Consistent with past research, for example, the team tracked down changes allowing for spread between brain cells that did not rely on specific cellular receptors. Instead, both subpopulations were marked by alterations affecting fusion and hemagglutinin viral envelope protein-coding genes, leading to changes in the virus' ability to fuse with and enter host cells.

"We found that the viral membrane fusion apparatus changed considerably during brain spread, but the viral polymerase was well conserved," Cattaneo said.

These and other findings hinted at the potential benefits of targeting the measles polymerase to treat SSPE, while highlighting the potential pitfalls of focusing on the virus' fusion machinery, which appeared to undergo relatively rapid evolutionary shifts in the brain.

More generally, the authors noted that the current analyses "indicate that collective infectious units can be an important evolutionary unit for [measles virus] brain colonization and raise profound questions about the importance of collective infectious units in human disease."