The Ebola virus – one of the deadliest diseases known to man – has been appearing throughout the world with increasing frequency over the last two years. There is no cure and no vaccines exist for the disease, which has a fatality rate of up to 90 percent.
However, in a new study published in the journal Cell, scientists are revealing a breakthrough discovery regarding the molecular mechanism behind the Ebola virus, possibly paving the way for effective treatments in the future.
For the past 10 years, researchers believed they had a good understanding of this mechanism. Yet certain questions about how the virus operated and spread remained, prompting study author Erica Ollmann Saphire and her colleagues to examine the virus further.
“We’d been looking at other proteins in the virus and how they work. It’s a fascinating virus and only has seven genes – compared to a human with 20,000 genes,” Saphire, professor in the department of immunology and microbial science at the Scripps Research Institute in La Jolla, Calif., said. “How does this virus do everything it needs to do with only a couple of tools in its tool kit?”
Ebola is highly virulent, spreading rapidly when a person comes into contact with bodily fluids of an infected person or animal. People who contract the infection initially come down with a high fever, headache and body aches. But the disease progresses quickly and soon begins to replicate in extremely high concentrations within the blood.
“The virus replication causes tissue destruction, and the virus protein causes you to clot where you aren’t supposed to and bleed where you aren’t supposed to,” Saphire said. “You get disseminated intravascular coagulation, which causes vomiting, diarrhea and essentially you die from shock.”
Upon examining the Ebola VP40 protein, the biological mechanism at the root of the lethal disease, Saphire and her colleagues discovered something shocking: the protein which was previously thought to be a monomer, or single molecule, was actually a dimer, a pair of molecules.
“We’d thought that the structure of the protein was solved,” Saphire said. “That the structure available must resemble how the protein builds the virus, because a central dogma that we all learn as biochemistry students is that the sequence of a protein dictates its fold and the fold dictates its function. A one-way destiny of sequence to function. It was a surprise that this sequence makes so many structures for so many functions.”
Thanks in part to improved technologies, Saphire and her team were able to see the Ebola VP40 protein with more clarity than previous researchers. They ultimately found its structure and behavior were different when compared to typical monomer proteins.
“The virus life cycle is it’s floating around, finds a cell, dives in, makes copies of all the protein and then those assemble into new viruses and bud out,” Saphire said.
However, researchers noticed that the Ebola VP40 protein was shifting shapes as it made its way through the various stages of virus assembly before branching out and spreading to other cells, in a way never before seen.
“The analogy we like to use is (that it’s like) a transformer. It has all the right parts, but one stage is born as a robot…Then…it unfolds and refolds,” Saphire said. “What we need to do is design drugs to prevent it from changing.”
Currently, no treatments exist for the Ebola virus and patients can only be offered supportive care as the disease makes its way through their bodies. Yet, this discovery opens up the possibility of developing treatment options that could kill the virus before it spreads.
“In terms of practical use, we see it uses structures A, B and C, and now we know that a drug that inhibits A can kill it, B can kill it or C can kill it,” Saphire said. “So we now have all of these opportunities to kill the virus.”
Saphire says this knowledge could someday be used to cure people infected with the virus. Additionally, prophylactic drugs could be developed, which would prove useful to people frequently sent to high-risk outbreak areas, such as employees of the Centers for Disease Control and Prevention (CDC).
Furthermore, now that researchers have discovered this protein, they are interested in exploring whether it exists in other viruses or diseases as well.
“With cancer, where the state of the cell goes from healthy to cancerous, could that change be because of the protein adopting a different structure and we have never thought to look for that before?” Saphire asked. “This speaks to how information can be encoded and proteins can do more than we ever thought.”
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