Summary: Measles virus that persists in the body can cause mutations in the F protein, which controls how the virus infects cells. The altered protein interacts with its normal form, which has the potential to infect the brain.

Source: Kyushu University

Japanese researchers have discovered a mechanism for how the measles virus causes sclerosing panencephalitis, or SSPE, a rare but fatal neurological disorder that can occur several years after measles infection.

Although the common measles virus cannot infect the nervous system, the team found that viruses that persist in the body can cause mutations in a key protein that controls how it infects cells. The altered proteins have the potential to infect the brain by interacting with their normal form.

Their findings were reported in the journal Advances in science.

If you are of a certain age, you may have had measles as a child. Many born after the 1970s never got it because of vaccinations. The disease is caused by the virus of the same name, which is one of the most contagious pathogens to date. The World Health Organization estimates that by 2021, nearly nine million people will be infected with measles worldwide, and the death toll will reach 128,000.

“Although available, the recent COVID-19 outbreak has set back vaccines, especially in the Global South,” said Yuta Shirogane, assistant professor at Kyushu University’s Faculty of Medical Sciences. “SSPI is a rare but fatal condition caused by the measles virus. “However, the common measles virus does not have the ability to spread through the brain, so it is not clear how it causes encephalitis.”

A virus infects cells through a series of proteins released from their surface. Usually, one protein first facilitates the attachment of the virus to the cell surface, and then another surface protein triggers a reaction that allows the virus to enter the cell, leading to infection. So what a virus can or can’t infect depends on the cell type.

“Usually, the measles virus only infects the immune and epithelial cells, causing fever and rash,” Shrogan continues. “So in patients with SSPE, the measles virus must remain in their body and mutate, then acquire the ability to infect neurons. RNA viruses like measles mutate and evolve at high rates, but how it evolved to infect neurons was a mystery.”

A key player in allowing the measles virus to infect the cell is a protein called the fusion protein, or F protein. In previous studies, the team showed that certain mutations in the F protein put it in a ‘hyperfusongenic’ state, allowing it to fuse at nerve synapses and infect the brain.

In their recent study, the team analyzed the genome of the measles virus from SSPE patients and found the accumulation of different mutations in the F protein. Interestingly, some mutations increase infection activity while others actually decrease it.

“This was surprising to see, but we found an explanation. When the virus infects a nerve, it affects it through ‘enblock transfer’ where many copies of the viral genome enter the cell,” Shirogan said. “In this case, the genome encoding the mutant F protein is transmitted simultaneously with the normal F protein genome, and both proteins can coexist in the infected cell.”

Based on this hypothesis, the team analyzed the binding activity of mutant F proteins in the presence of normal F proteins. Their results show that the fusion activity of a mutant F protein is suppressed by interference with normal F proteins, but that the interference is overcome by the accumulation of mutations in the F protein.

This shows the pattern in the study
Mutation of the F protein is key for measles virus to integrate and infect neurons. There are two main methods of such an infection. Initially, the fusion activity of the mutant F protein is inhibited due to interference from normal F proteins (black box). That interference is due to the accumulation of mutations and an increase in fusogenecity (orange box). In another case, a specific mutation in the F protein acts oppositely and reduces fusion activity, but conversely associates with F proteins that increase fusion activity (blue box). Thus, even mutant F proteins that appear unable to infect neurons can infect the brain. Credit: Kyushu University/Hidetaka Harada/Yuta Shirogane

In another case, the team found that a specific mutation in the F protein produced the opposite effect: reduced fusion activity. However, surprisingly, this mutant is able to cooperate with normal F proteins to increase fusion activity. Thus, even mutant F proteins that appear unable to infect neurons can infect the brain.

“It defies the ‘survival of the fittest’ model for viral transmission. Indeed, this phenomenon in which mutations disrupt and/or interact with each other is called ‘sociovirology’. It is still a new concept, but viruses have been observed to interact with each other as a group. It’s an exciting prospect,” explains Shirogane.

The team hopes their results will lead to the development of a treatment for SSPE, as well as elucidate common evolutionary mechanisms with viruses with a similar mode of infection to measles, such as the novel coronavirus and the herpes virus.

“There are many mysteries about 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 explain the mechanism of this disease,” Shrogane said.

So neurology and virology research news

Author: Raymond Turhun
Source: Kyushu University
Contact: Raymond Terhune – Kyushu University
Image: Image courtesy of Kyushu University/Hidetaka Harada/Yuta Shirogane.

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Preliminary study: Open Access.
Complex integration activity determines neurotropism of en bloc transmissible enveloped viruses.” by Yuta Shirogane et al Advances in science


Complex integration activity determines neurotropism of en bloc transmissible enveloped viruses.

Measles virus (MV), which is usually non-neurotropic, sometimes persists in the brain and causes chronic sclerosing panencephalitis (SSPE) several years after acute infection, serving as a model for persistent viral infections.

Persisting MVs have hyperfusogenic mutant fusion (F) proteins, which allow cells to fuse at synapses and “enblock transfer” between neurons.

Here we show that F protein fusogenicity during persistence is generally enhanced by cumulative mutations, but mutations that reduce fusogenicity can be selected against wild-type (non-neurotropic) MV genomes.

A substituted F protein derived from SSPE shows less fusogenicity than a protein containing some of the hyperfusogenic F proteins, but upon fusion with wild-type F protein, the fusogenicity of the former F protein is enhanced, whereas that of the latter is very close. Canceled.

These findings advance understanding of the long-term course of MeV neuropathogenicity and provide critical insight into genotype-phenotype relationships of enblock-transmitted viruses.

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