In 2013–2016, an epidemic of Ebola virus disease swept through western Africa, killing more than 11,000 people. While the world trembles at the thought of the next outbreak, researchers worldwide are struggling to find a cure, but there is no effective treatment yet. Danish basic researchers were searching for knowledge in a completely different direction when they stumbled on a spectacular discovery. New insight on how the Ebola virus hijacks human cells has enabled the researchers to foil attacks by the Ebola virus and other viruses.
It starts with influenza-like exhaustion, fever and reduced appetite. This is quickly followed by vomiting, diarrhoea and stomach pains – then breathing difficulties, headache and disorientation. After another 5–7 days, internal and external bleeding begins, accompanied by vomiting blood and faecal bleeding. Nine of ten people with Ebola virus disease die after 6–16 days of low blood pressure resulting from loss of body fluids. There has been no cure and no effective vaccine against the Ebola virus – until now. However, somewhat by serendipity, Danish researchers are now on the trail of Ebola’s Achilles heel.
“We were investigating an enzyme called PP2A-B56 that is involved in regulating human metabolism. We used our computers to identify proteins from other organisms that could interact with this enzyme and got a surprise. Ebola. It turns out that the Ebola virus hijacks the PP2A-B56 enzyme and uses it to replicate itself. So when we inhibited PP2A-B56, the Ebola virus could no longer infect human cells,” explains Thomas Kruse, a main author from the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.
Ebola virus falls apart
When viruses attack, they need help from their host because they carry a limited arsenal of tools. The Ebola virus therefore needs to borrow tools from infected people so that it can create more virus particles and more infection. Without this help, the body would rapidly neutralize the virus.
“The Ebola virus has to copy all its proteins and then its genetic material to be able to spread to other cells. But, to copy – or transcribe – its genome, it needs to activate a viral transcription factor, VP30, and this requires cleaving a phosphate group from VP30.”
The Ebola virus does not have the chemical scissors to cleave the phosphate group from VP30. The virus therefore has to borrow the phosphate scissors from its human host. This was precisely the enzyme that the Danish researchers were investigating in a basic research study of human metabolism. They discovered that the PP2A-B56 enzyme recognizes proteins that contain a specific amino acid sequence.
“Using a web-based database search engine, we routinely compared the amino acid sequence of human proteins with those of other organisms. The search revealed that the PP2A-B56 phosphatase can bind to a sequence in one protein in the Ebola virus called NP. The NP protein also binds to VP30, which is activated when all three are connected. Conversely, if VP30 is not activated, the Ebola virus will be eradicated because it cannot copy and spread itself.”
A matter of life and death
When the Copenhagen-based researchers realized their discovery, they contacted Ebola experts from Philipps-Universität Marburg to see whether they could inhibit the virus by inhibiting the PP2A-B56 enzyme in human cells, so that the Ebola virus could no longer use it.
“By inhibiting the enzyme, we removed the first link in a long process that ends with the Ebola virus spreading through the human body. We can see that it works. In cell cultures the Ebola virus infection were reduced 10 fold already after 24 hours when we inhibited the PP2A-B56 enzyme.”
The researchers now hope to proceed with experiments on animals and thereby develop a drug that can both cure people with the disease and prevent the otherwise extremely contagious Ebola virus from spreading. Today there is no effective treatment. The only hope is that each person’s immune system can vanquish the infection.
“The greatest challenge is to find a way of inhibiting PP2A-B56 well enough so that the Ebola virus dies without the patient experiencing severe side-effects. However, because the Ebola virus is extremely contagious and the disease is fatal, people are likely to put up with relatively great side-effects because it really is a matter of life and death.”
This fact will presumably also make the process of getting approval for a cure for Ebola virus disease easier and more rapid. The researchers have only tested the drug in cell cultures, so there is still some way to go before the results can be used to treat people who are infected. Initially, the researchers hope to test it on animals. The potential of the new discovery may also prove to be greater than just the Ebola virus.
The structure of the Ebola virus is similar to other filoviruses such as the Lloviu and Marburg viruses. However, it remains to be determined whether the same mechanisms apply to them, although potentially the same drug could be used to treat several types of viral infections.
“The Ebola virus nucleoprotein recruits the host PP2A-B56 phosphatase to activate transcriptional support activity of VP30” has been published in Molecular Cell. Several of the authors are employed at the Novo Nordisk Foundation Center for Protein Research.