Japanese researchers have discovered the mechanism behind the development of subacute sclerosing panencephalitis (SSPE), a fatal neurological disorder that can occur years after measles infection.
The measles virus “collaborates” with itself to cause deadly encephalitis
Scientists have discovered a new mechanism for how the measles virus causes a rare but fatal neurological disorder, subacute sclerosing panencephalitis.
Researchers in Japan have revealed the mechanism of how the measles virus can cause subacute sclerosing panencephalitis, or SSPE, a rare but fatal neurological disorder that can develop several years after infection with measles.
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 cells are infected. The transgenic proteins can interact with their normal form, making them capable of infecting the brain. Their findings will be published today (January 27) in the journal Science advances
Science Advances.
If you are of a certain age, you may have had measles as a child. Many of those born after the 1970s never got it thanks to vaccines. This condition is caused by a virus of the same name, which is one of the most infectious pathogens to this day. The World Health Organization estimates that nearly nine million people worldwide contracted measles in 2021, with the death toll reaching 128,000.
The mutation in the F protein is key for the measles virus to fuse and infect nerve cells. There are two main strategies for such infection. Initially, the fusion activity of the mutant F protein is suppressed due to interference from normal F proteins (black box). This overlap is overcome by accumulation of mutations and increased compactness (orange square). In another case, a different mutation in the F protein acts oppositely and reduces fusion activity, but conversely cooperates with the normal F proteins increasing fusion activity (blue box). Thus, even mutant F proteins that seem unable to infect neurons can infect the brain. Credit: Kyushu University/Hidetaka Harada/Yuta Shirogane
“Although it is available, it is only recently
COVID-19 The pandemic has set back vaccinations, especially in the Global South,” explains Yuta Shirogane, assistant professor at Kyushu University’s College of Medical Sciences. “SSPE is a rare but fatal condition caused by the measles virus. However, the normal measles virus does not have the ability to multiply in the brain, and so it is not clear how it causes encephalitis. “
The virus infects cells through a series of proteins that protrude from their surface. Normally, one protein will first facilitate the virus to attach to the cell surface, and then another surface protein will cause a reaction that allows the virus to enter the cell, resulting in infection. Therefore, what a virus can or cannot infect can depend greatly on the cell type.
“Measles virus usually only infects immune and epithelial cells, causing fever and rash,” Shirogane continues. Therefore, in patients with SSPE, the measles virus must have remained in their bodies and mutated, then gaining the ability to infect neurons.
RNA Viruses like measles mutate and evolve at very high rates, but the mechanism of their evolution to infect neurons has been a mystery.”
Measles virus is an enveloped virus that carries a lipid bilayer. The bilayer contains the receptor-binding hemagglutinin (H) protein and the fusion protein (F). For infection to occur, the H protein first binds to a receptor on the target cell, and then the F protein changes shape to fuse the membranes. Credit: Kyushu University/Hidetaka Harada/Yuta Shirogane
The key player in allowing the measles virus to infect a cell is a protein called a fusion protein, or F protein. In the team’s previous studies, they showed that certain mutations in the F protein put it into a ‘hypercoherence’ state, allowing it to fuse into synapses and infect the brain.
In their latest study, the team analyzed the measles virus genome from SSPE patients and found that various mutations had accumulated in their F protein. Interestingly, some mutations may increase infection activity while others actually decrease it.
“It was surprising to see this, but we found an explanation for this. When a virus infects a nerve cell, it infects it through ‘block transmission’, where multiple copies of the viral genome enter the cell,” Shirogane continues. “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 the mutant F proteins when the normal F proteins were present. Their results showed that the fusion activity of the mutant F protein is suppressed due to interference from normal F proteins, but this interference is overcome by the accumulation of mutations in the F protein.
When an F protein stimulates membrane fusion at a synapse, multiple measles virus genomes are simultaneously transmitted to the next neuron. This phenomenon is known as “mass transfer”. Under this condition, the normal and mutant genomes translocated together simultaneously, resulting in the formation of normal and mutant F proteins together in an infected cell. Credit: Kyushu University/Hidetaka Harada/Yuta Shirogane
In another case, the team found that a different set of mutations in the F protein lead to exactly the opposite result: a decrease in fusion activity. However, to their surprise, this mutation can actually cooperate with normal F proteins to increase fusion activity. Thus, even mutant F proteins that seem unable to infect neurons can infect the brain.
It is almost equivalent to the “survival of the fittest” model of viral replication. In fact, this phenomenon in which mutations interfere and/or cooperate with each other is called “sociology”. This is still a new concept, but viruses have been observed interacting with each other as a group. It’s an exciting prospect, Shirogane explains.
The team hopes their findings will help develop treatments for SSPE, as well as elucidate common evolutionary mechanisms for viruses that have infection mechanisms similar to measles such as novel coronaviruses and herpes viruses.
There are many mysteries in the mechanisms by which viruses cause disease. Since I was a medical student, I was interested to know how the measles virus caused SSPE. I’m glad we were able to clarify the mechanism of this disease,” concludes Shirogane.
Reference: “Collective fusion activity determines neural orientation of an enveloped virus transmitted across a mass” Yuta Shirogane, Hidetaka Harada, Yuichi Hirai, Ryuichi Takemoto, Tateki Suzuki, Takao Hashiguchi and Yusuke Yanagi, Jan. 27, 2023, Available Here. Science advances.
DOI: 10.1126/sciadv.adf3731
