16 January 2018 - PRESS RELEASE

European research team outwits Ebola virus

Researchers have specifically inhibited Ebola virus replication in a laboratory investigation. A new imaging procedure enables testing of potential drugs.

Ebolaviren_NIAID.jpg

The digitally-colorized scanning electron microscopic (SEM) image depicts numerous filamentous Ebola virus particles (blue) budding from a chronically-infected cell.© National Institute of Allergy and Infectious

An artificially produced inhibitor curbs Ebola virus replication and could be used to develop drugs for life-threatening Ebola virus epidemics. An European team of scientists bases this hope on findings from experiments in which the virus was prevented from misusing an enzyme from infected cells for its own purposes. The team reports its findings in the current online issue of the science journal “Proceedings of the National Academy of Sciences of the United States of America” as well as in the journal “Molecular Cell”.

Ebola virus causes life-threatening febrile disease which is fatal in most cases. “The largest known Ebola virus epidemic ended in 2016, in West Africa, after causing over 11,000 deaths,” says virologist Prof Stephan Becker from the Philipps-University Marburg, senior author of the new publication; “To date, no cure for the disease exists.” In a German Center for Infection Research (DZIF) project, Becker’s research group collaborated with cell biologists and biochemists from Denmark and Ireland in order to close this research gap. The study has identified a molecule that could serve as a target site for future drugs, and hence opens up new possibilities for treating Ebola fever. 

The virus protein VP30 plays a key role in Ebola virus replication: it either promotes replication of the entire viral genome or ensures that individual genes become readable and are subsequently transcribed into proteins, depending on its existing chemical form.

Switching from one function to the other is accomplished by attaching phosphate groups to specific VP30 sites. Up to now, how these processes are regulated has been unknown.

Becker and his team have now shown that, of all things, an enzyme from the infected host cell called PP2A-B56 is responsible for this dephosphorylation. Becker refers to this as “enzyme kidnapping” by the virus. The virus uses NP, its nucleoprotein, to bring the host phosphatase and VP30 closer together. Phosphatase and VP30 have contact sites on the nucleoprotein, which are located next to each other. Both fit into their respective contact sites like plugs into sockets.

The scientists conducted cleverly designed experiments to demonstrate how dephosphorylation occurs. The research team created a molecular duplicate that docks onto the target site for phosphatase just as well as the nucleoprotein does. This duplicate displaces the nucleoprotein, resulting in a separation of the forced bond between VP30 and PP2A-B56. With this manoeuvre, the scientists prevent the host enzyme from removing the phosphate attachments from the virus protein VP30.

As the experiment findings have shown, replication under these circumstances becomes more difficult for the virus than when VP30 is in contact with the host phosphatase. The more phosphatase inhibitor is applied, the fewer genomes the virus produces. This substantially reduces viral replication. “Our findings show that artificially produced phosphatase inhibitors supress Ebola virus infection,” explains Dr Nadine Biedenkopf, one of the co-authors of the study.

“Inhibition of this phosphatase may offer a strategy to target Ebola virus infections,” the authors write. “An advantage of targeting a host factor rather than viral proteins is that resistance to inhibitors is less likely to occur.” “However, it is also clear that an obvious down side to targeting an essential protein such as PP2A-B56 is the potential for side effects on vital cellular processes. Nevertheless, the inhibition of essential protein phosphatases has been successfully used in the clinic for many decades.”  In order to enable testing of new inhibitors against the Ebola virus, Becker’s research group has also established live-cell imaging procedures that can be used to track movements of particles similar to viruses. “This will also be used to examine virus and cell interfaces to identify further potential target sites for antiviral agents,” explains Becker.

Professor Stephan Becker heads Philipps-University Marburg’s Institute of Virology and coordinates the research field “Emerging Infections” at the German Center for Infection Research (DZIF). The Marburg Institute houses one of Europe’s highest biosafety level laboratories in which dangerous pathogens such as Ebola and Marburg viruses can be investigated. The study was funded by the Marburg Collaborative Research Centre 1021 of the German Research Foundation, amongst others.

Original publications

Thomas Kruse, Nadine Biedenkopf, Emil Peter Thrane Hertz & al.: The Ebola Virus Nucleoprotein Recruits the Host PP2A-B56 Phosphatase to Activate Transcriptional Support Activity of VP30, Mol. Cell 2017,
DOI: doi.org/10.1016/j.molcel.2017.11.034

Yuki Takamatsu, Larissa Kolesnikova & Stephan Becker: Ebola virus proteins NP, VP35, and VP24 are essential and sufficient to mediate nucleocapsid transport, Proc. Natl. Acad. Sci. USA 2018, DOI: www.pnas.org/cgi/doi/10.1073/pnas.1712263115

To the Marburg press release (in German)  

Contact
Professor Stephan Becker,
Institute of Virology
DZIF research field “Emerging Infections”
T 06421 28 66253
E-mail

DZIF-Press Office
Karola Neubert and Janna Schmidt
T +49 6181 1170/1154
E-mail



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