Ebola: Potential Molecular Targets For Drug Development

By Simon Hackett

Yesterday, December 1, marked exactly one year since the start of the Ebola outbreak – the viral epidemic currently sweeping West Africa that has claimed 5000 deaths to date. The WHO has recently described the epidemic as “the most severe acute public health emergency seen in modern times."¹ In recent months, the virus has spread to countries further afield, via infected aid workers, including Spain and the USA. What sets this epidemic apart from other viral epidemics, such as influenza and HIV, is not only the staggeringly high fatality rate of 60-70%, but the devastating symptoms associated with the disease.

The Ebola epidemic is spread, as the name suggests, by the Ebola virus, which belongs to a group of viruses known as filoviruses. It is thought that Ebola originated in fruit bats² however, the sequence of events that led to the transmission from bat to human has not been pinpointed precisely. The first ever outbreak of Ebola was during 1976 in Sudan and since, there have been outbreaks in 1995 in the Democratic Republic of Congo, and again in 2007 (but on much smaller scales than the current outbreak).

The power of evasion

Like most viruses, Ebola attaches to specific cell surface receptors on the cell membrane, in particular endothelial cells³ and macrophages⁴.  The viral envelope then fuses with the cell membrane resulting in the release of the virus into the cell cytosol. Following entry into the cell, the Ebola virus replicates at an extremely rapid rate that overwhelms both the capacity of the cell to synthesise new proteins, as well as the host immune system. Given the preference for the virus to target immune cells such as monocytes, dendritic cells and macrophages, massive amount of inflammatory cytokines are released such as IL-1β, TNFα and IL-6.  The pro-inflammatory state caused by the release of these cytokines, along with the destruction of endothelial cells results in damage to blood vessels and massive hemorrhaging. However, despite the substantial release of inflammatory cytokines by host cells, the Ebola virus manages to evade interferon responses by expressing the proteins VP35 and VP24 which down-regulate interferon production⁵. Researchers have quantified the levels of interferons in infected animals using ELISAs specific for interferons and pro-inflammatory cytokines. It is this feature of the virus, which allows the Ebola to evade destruction by the immune system.

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Limited options

Despite much research into the pathophysiology of the virus, treatment options are currently limited. Physicians have had some success treating patients with the experimental drug ZMapp⁶, which consists of three chimeric monoclonal antibodies⁷, originally derived from virally infected mice and produced in the tobacco plant^6. However, the supplies of ZMapp are limited and are incredibly expensive: a significant hurdle for a disease primarily affecting third world countries. Furthermore, ZMapp has not been subjected to the rigorous clinical testing drugs must usually pass to approve their use in the clinic. Other treatments for Ebola are often supportive and a targeted treatment for the disease is much needed.

Another approach

As well as the family of IFITM proteins, the protein BST2 (also known as CD317) has also been implicated in host protection against viruses. BST2 is expressed on B cells, plasma cells and plasmacytoid dendritic cells and its expression results from interferon release. BST2 has been shown to inhibit the diffusion of viral particles after budding from infected cells including Ebola⁹. With respect to therapeutic targeting, Yasuda⁹ suggested the induction of expression of BST2 may prove a novel approach in inducing an antiviral response in infected individuals.

It is clear that Ebola presents a major humanitarian and scientific challenge to both governments and researchers. Through identifying the molecular mechanisms by which Ebola infects and destroys cells, it is hoped that targeted therapies can be developed to control this devastating disease and made more accessible to countries where they are needed most.

Antibodies related to Ebola virus research