Measles Virus "Cooperates" with Itself to Cause Encephalitis

FUKOKA, JAPAN — Researchers in Japan have uncovered the mechanism behind how measles virus causes subacute sclerosing panencephalitis (SSPE)—a rare but fatal neurological disorder that can occur several years after a measles infection.

Although the normal form of the measles virus cannot infect the nervous system, the team found that viruses that persist in the body can develop mutations in a key protein that controls how they infect cells. The mutated proteins can interact with their normal form, making them capable of infecting the brain. Their findings were reported in the journal Science Advances.

Measles—one of the most contagious pathogens to this day—is caused by the virus of the same name. The World Health Organization estimates that nearly nine million people worldwide were infected with measles in 2021, with the number of deaths reaching 128,000.

"Despite its availability, the recent COVID-19 pandemic has set back vaccinations against measles, especially in the Global South," explained Yuta Shirogane, MD, PhD, assistant professor at Kyushu University's Faculty of Medical Sciences. "SSPE is a rare but fatal condition caused by measles virus. However, the normal measles virus does not have the ability to propagate in the brain, and thus it is unclear how it causes encephalitis."

A virus infects cells through a series of proteins that protrude from its surface. Usually, one protein will first facilitate the virus to attach to a cell's surface, then another surface protein will cause a reaction that lets the virus into the cell, leading to an infection. Therefore, what a virus can or cannot infect can depend heavily on the type of cell.

"Usually, the measles virus only infects your immune and epithelial cells, causing the fever and rash," said Shirogane. "Therefore, in patients with SSPE, the measles virus must have remained in their body and mutated, then gained the ability to infect nerve cells. RNA viruses, like the measles virus, mutate and evolve at very high rates, but the mechanism of how it evolved to infect neurons has been a mystery."

The key player in allowing the measles virus to infect a cell is a protein called fusion protein (F protein). In the team's previous studies, they showed that certain mutations in the F protein put it in a "hyperfusongenic" state, allowing it to fuse into neural synapses and infect the brain.

In their latest study, the team analyzed the genome of the measles virus from SSPE patients and found that various mutations had accumulated in their F protein. Interestingly, certain mutations would increase infection activity while others actually decreased it.

"This was surprising to see, but we found an explanation. When the virus infects a neuron, it infects it through 'en bloc transmission,' where multiple copies of the viral genome enter the cell," continues Shirogane. "In this case, the genome encoding the mutant F protein is transmitted simultaneously with the genome of the normal F protein, and both proteins are likely to coexist in the infected cell."

Based on this hypothesis, the team analyzed the fusion activity of mutant F proteins when normal F proteins were present. Their results showed that the fusion activity of a mutant F protein is suppressed due to interference from the normal F proteins, but that interference is overcome by the accumulation of mutations in the F protein.

In another case, the team found that a different set of mutations in the F protein results in a completely opposite result: a reduction in fusion activity. However, to their surprise, this mutation actually cooperated with normal F proteins to increase fusion activity. Thus, mutant F proteins that appear to be unable to infect neurons can still infect the brain.

"It is almost counter to the 'survival of the fittest' model for viral propagation. In fact, this phenomenon where mutations interfere and/or cooperate with each other is called 'sociovirology.' It's still a new concept, but viruses have been observed to interact with each other like a group. It's an exciting prospect," explains Shirogane.

The team hopes that their results will help develop therapeutics for SSPE and elucidate the evolutionary mechanisms in viruses that have similar infection mechanisms to the measles virus, such as novel coronaviruses and herpesviruses.

"There are many mysteries in the mechanisms by which viruses cause diseases. Since I was a medical student, I was interested in how the measles virus caused SSPE. I am happy that we were able to elucidate the mechanism of this disease," concludes Shirogane.

Along with Shirogane, the other authors of "Collective fusion activity determines neurotropism of an en bloc transmitted enveloped virus" include Hidetaka Harada, Yuichi Hirai, Ryuichi Takemoto, Tateki Suzuki, Takao Hashiguchi, Yusuke Yanagi.

- This press release was originally published on the Kyushu University website.