Overview: The measles virus that persists in the body can develop mutations in the F protein, which controls how the virus infects cells. The mutated protein can interact with its normal form, allowing it to infect the brain.
Source: Kyushu University
Researchers in Japan have discovered the mechanism of how the measles virus can cause subacute sclerosing panencephalitis, or SSPE, a rare but deadly neurological disorder that can appear several years after a measles infection.
While 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 determines how they infect cells. The mutated proteins can interact with their normal form, allowing them to infect the brain.
Their findings were reported in the journal Scientific progress.
If you are of a certain age, you may have contracted measles as a child. Many born after the 1970s never got it thanks to vaccines. The condition is caused by the virus of the same name, which remains one of the most contagious pathogens to this day. The World Health Organization estimates that by 2021 nearly nine million people worldwide were infected with measles, with the death toll rising to 128,000.
“Despite availability, the recent COVID-19 pandemic has slowed vaccination rates, especially in the South,” explained Yuta Shirogane, assistant professor in the Faculty of Medical Sciences at Kyushu University. “SSPE is a rare but deadly condition caused by the measles virus. However, the normal measles virus does not have the ability to spread in the brain and therefore it is unclear how it causes encephalitis.”
A virus infects cells through a series of proteins that protrude from the surface. Usually, one protein causes the virus to attach to the cell surface first, then another surface protein triggers a reaction that allows the virus to enter the cell, leading to an infection. What a virus can or cannot infect can therefore strongly depend on the type of cell.
“Usually, the measles virus only infects your immune system and epithelial cells, causing the fever and rash,” Shirogane continues. “Therefore, in patients with SSPE, the measles virus must have remained in their bodies and mutated, after which it gained the ability to infect nerve cells. RNA viruses like measles mutate and evolve at very fast 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 a fusion protein, or F protein. In previous studies by the team, they showed that certain mutations in the F protein put it in a ‘hyperfusonogenic’ state, allowing it to fuse with neural synapses and infect the brain.
In their latest study, the team analyzed the measles virus genome of SSPE patients and found that several mutations had accumulated in their F protein. Interestingly, certain mutations would increase infection activity, while others actually reduced it.
“This was surprising to see, but we found an explanation. When the virus infects a neuron, it infects it via “en bloc transmission,” where multiple copies of the viral genome enter the cell,” Shirogane continues. “In this case, the genome encoding the mutant F protein is transferred 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 fusion activity of a mutant F protein is suppressed by 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. To their surprise, however, this mutation can interact with normal F proteins to increase fusion activity. So even mutant F proteins that don’t appear to be able to infect neurons can still infect the brain.
“It almost goes against the ‘survival of the fittest’ model of viral spread. In fact, this phenomenon of mutations interfering and/or working together is called “sociovirology.” It is still a new concept, but viruses have been observed interacting as a group. It’s an exciting prospect,” explains Shirogane.
The team hopes their results will help develop therapies for SSPE, as well as elucidate the evolutionary mechanisms common to viruses that have similar mechanisms of infection to measles, such as novel coronaviruses and herpesviruses.
“There are many mysteries in the mechanisms by which viruses cause disease. Ever since I studied medicine, I’ve been interested in how the measles virus caused SSPE. I am pleased that we have been able to elucidate the mechanism of this disease,” concludes Shirogane.
About this neurology and virology research news
Writer: Raymond Terhune
Source: Kyushu University
Contact: Raymond Terhune – University of Kyushu
Image: The image is credited to Kyushu University/Hidetaka Harada/Yuta Shirogane
Original research: Open access.
“Collective Fusion Activity Determines Neurotropism of an En Bloc Transmitted Enveloped Virus” by Yuta Shirogane et al. Scientific progress
Collective fusion activity determines neurotropism of an en bloc transmitted enveloped virus
The measles virus (MeV), which is usually non-neurotropic, sometimes persists in the brain and causes subacute sclerosing panencephalitis (SSPE) several years after acute infection, and serves as a model for persistent viral infections.
The persistent MeVs have hyperfusogenic mutant fusion (F) proteins that likely enable cell-cell fusion at synapses and “en bloc transmission” between neurons.
We show here that during persistence, fusogenicity of the F protein is generally enhanced by cumulative mutations, but mutations that paradoxically reduce fusogenicity can be selected in addition to the wild-type (non-neurotropic) MeV genome.
A mutant F protein with SSPE-derived substitutions shows lower fusogenicity than the hyperfusogenic F protein containing some of those substitutions, but the co-expression of the wild-type F protein enhances the fusogenicity of the first F protein, while that of the latter was almost abolished.
These findings advance the understanding of the long-term process of MeV neuropathogenicity and provide critical insight into the genotype-phenotype relationships of viruses transmitted en bloc.