Two biochemical pathways critical for the Ebola virus to infect have been blocked in cell-culture experiments.
The Ebola virus epidemic in West Africa, the largest in history, still remains in the news today. First reported in December 2013, the CDC estimates 27,678 cases of infections with the total death count at 11,276.Although the World Health Organization recently declared Liberia to be 'free of Ebola', the deadly disease is still rife in parts of Africa.
Recent analysis has stated that global aid in response to the threat has "fallen short." There are many vaccines currently being tested, although none at this time are available for clinical use. However, scientists may have now discovered a critical early step in the development of a vaccine.
The findings, published in the journal Drug Discovery Research, saw researchers at the University of Texas Medical Branch (UTMB) at Galveston, TX, take a new approach to tackling the life-threatening virus.
By using powerful computational and analytical techniques, researchers chose to focus more on the host cell than the virus. Lead author Prof. Robert Davey explains:
"The premise for this work is that the virus is essentially nothing without a cell. It needs to rely on many cell proteins and factors for it to replicate. The idea is that if we can suppress the expression of those cell proteins for just a short time, we can then stop the disease in its tracks."
To identify the critical proteins, researchers conducted large-scale screening experiments using sets of cells treated with a small interfering Ribonucleic acid (siRNA), a tool commonly used to induce the silencing of a specific protein gene.
Researchers identified 735 different genes that might produce proteins critical for the Ebola infection. They then added a "pseudo-type" Ebola virus - artificially created virus particles made by wrapping Ebola envelope proteins around a core of genetic material from another virus.
This creates a virus that behaves like Ebola but is not strong enough to be harmful, and is, therefore, safe to test.
Prof. Davey explains the challenges the researchers encountered: "We got a number of hits, quite a lot of places where the virus wasn't infecting the cells. The problem was then to understand what those hits meant."
Two critical biochemical reactions identified
To understand the influx of this new data, researchers used a newly developed statistical algorithm designed especially to prioritize the results of siRNA screens.
Further computational analysis was utilized and scientists discovered two networks of biochemical reactions that seemed particularly critical for the virus to enter the cells - the PI3 kinase pathway and the CAMK2 pathway.
There are drugs currently available to block both pathways and researchers decided to press on to see if they would interfere with the Ebola infection of cells. They tested both the virus pseudo-types and the Ebola Zaire virus. The latter is associated with particularly high mortality rates and was only tested in strict laboratory conditions to ensure maximum containment.
Researchers found that virus titers for the real Ebola virus dropped by 65% when the PI3 kinase inhibitor was stopped. Even more promising was that when the CAMK2 function was blocked, the Ebola virus "stopped dead".
Prof. Davey believes the developments show "a lot of potential for future pharmaceutical exploitation."