It might be hard to believe, but there was a time when nearly all children in the United States contracted measles before the age of 15. This was the state of the country before the measles vaccine became available in 1963. Before the vaccine, an average of 3 to 4 million people annually got infected, among whom a small percent suffered from a lethal form of the disease, termed sub-acute sclerosing panencephalitis (SSPE), characterized by significant brain swelling. While vaccination can prevent SSPE development, scientists are still dissecting the “how” of measles virus infection in the brain. Graduate student Will Hannon in the Basic Sciences Division at Fred Hutchison Cancer Center explained, “Ordinarily, measles doesn’t infect the brain. The cells in the brain don’t express either of measles’ canonical receptors that the virus needs to enter cells. Yet, in rare cases, measles overcomes this barrier. The mechanisms underlying this dramatic shift in tissue specificity are a long-standing mystery in the field.” Hannon and Dr. Alison Feder, an Assistant Professor in Genome Sciences at UW and Public Health Sciences at Fred Hutchinson Cancer Center, wanted to understand the dynamics and genetic diversity of measles virus infection in the brain. Their study of measles virus genetic diversity, recently published in PLoS Pathogens, revealed two dominant virus populations in the brain of a deceased individual with lethal SSPE. Interestingly, mutations in these two strains likely enabled enhanced cell-to-cell fusion for receptor-independent cell-to-cell viral transfer.
“While other researchers had previously identified mutations in measles that they hypothesized allowed it to infect the brain, the dynamics through which those mutations arose and enabled their spread are unknown,” shared Hannon. “We investigated measles sequences from multiple locations in the brain of someone who succumbed to measles SSPE.” Like a watermark on a piece of paper, the genetic code of the virus provides a clue to how it came to establish infection and spread throughout the brain and “we noticed extensive viral genomic diversity,” noted Hannon.
“This diverse population of viruses contained viral variants with mutations in the receptor-binding and fusion machinery that previous research had suggested might play a crucial role in measles’ ability to infect the brain. Surprisingly, these mutations tended to exist at intermediate frequencies almost everywhere in the brain rather than dominating the virus population as you might expect from a mutation that confers a strong selective advantage.” One explanation for this observation could be that these mutations, while enabling the virus to infect and spread in the brain, may simultaneously hinder viral replication. “We reasoned that frequency-dependent selection for the optimal level of cell fusion – enabled by the co-infection of distinct viral variants – could explain our observation.” Herein, two viral variants may provide something that the other is lacking to enable virus production and spread in the brain.
The researchers were also curious about how the measles virus spread throughout the brain of this individual. To this end, several anatomical sections of the brain—the frontal cortex, parietal lobe, internal capsule, brain stem, and cerebellum—were sampled and analyzed for total viral RNA. The frontal cortex and parietal lobe had the highest total viral RNA levels, meaning that more virus was present at these sites likely due to greater viral replication. Conversely, the total viral RNA was low in the cerebellum, a site close to the brainstem. These findings suggest that more viral replication occurred in the parietal lobe than in the cerebellum. Sequence analysis of viral variants at these sites also informed on how measles virus spread might have occurred in this brain. The researchers were looking for branch points or points in which the genetic code of the virus changes to create two new branches in a family tree. The viral genomes with the earliest branch point mutations, in which most of the measles genome is unchanged, were present in the frontal cortex, which is also a site of high viral replication. The occurrence of driver mutations—those that would enable receptor-independent spread of the virus in the brain—were found at every site, but more mutations accumulated at sites distal to the frontal cortex. With these and other insights, the researchers speculate that the virus entered the brain through the oropharyngeal route or olfactory nerve and became constrained in the frontal cortex because these cells lack the receptors needed for virus spread. Then, driver mutations occurred to enable the virus to spread to distal sites of the brain and accumulate more non-driver genetic diversity. This working model informs on the “how” of measles virus invasion and propagation in the brain to cause SSPE.
“Our work provides a unique example of cooperation between viral variants potentially driving disease,” summarized Hannon. One virus variant may not be sufficient to replicate and cause disease, thus co-infection with another variant may be required. “Although our observations suggest cooperation between distinct viral variants, further work in a model of measles infection is needed to confirm our hypotheses,” commented Hannon. These experiments will be the future directions of this collaborative research effort.
The spotlighted research was funded by the National Institutes of Health, the Mayo Clinic Graduate School of Biomedical Sciences, and the New Jersey Alliance for Clinical and Translational Science.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Dr. Alison Feder contributed to this work.
Yousaf I, Hannon WW, Donohue RC, Pfaller CK, Yadav K, Dikdan RJ, Tyagi S, Schroeder DC, Shieh WJ, Rota PA, Feder AF, Cattaneo R. 2023. Brain tropism acquisition: The spatial dynamics and evolution of a measles virus collective infectious unit that drove lethal subacute sclerosing panencephalitis. PLoS Pathog. 19(12):e1011817.