Drawing order from disorder to unravel Ebola’s lethality

The virulence of Ebola virus strains appears to be innately linked to the degree of disorder in proteins that form their nucleocapsids. Computational analysis has revealed that strains responsible for the most lethal outbreaks of Ebola show significantly higher levels of intrinsic protein disorder than less virulent strains, in a discovery that could constitute a major breakthrough in understanding the pathogen’s behaviour.

With over 27,000 confirmed, probable and suspected cases and more than 11,000 fatalities worldwide, the ongoing Ebola outbreak has resulted in considerably more casualties since late 2013 than all other outbreaks combined. There are no effective treatments or vaccines against the haemorrhagic fever that evinces Ebola infection; however, strains of the virus with drastically different virulence have emerged since the first outbreak in 1976, with fatality rates ranging from 25 to 90%.

In an effort to explain such radical variations in lethality, researchers Gerard Goh, from Goh’s BioComputing in Singapore, Keith Dunker, from the Indiana University School of Medicine in the US, and Vladimir Uversky, from the University of South Florida in the US, have computationally explored links between the virulence of different Ebola virus strains and their predicted protein structures. The group discovered that intrinsically disordered proteins (IDPs) encapsidating the virus’ genetic material appear to play a large role, with increasing levels of disorder correlating with greater virulence.

‘The discovery of molecular determinants of Ebola virus virulence has been elusive and we hope that our research is indicative of a turning point,’ says Goh. ‘Our findings seem to indicate that the secret lies in the nucleocapsid or, more specifically, its disorder’.

IDPs are distinguished from other proteins by their, at least partial, lack of a fixed three-dimensional structure. Although their existence was proposed more than 50 years ago, it is only since the recent advent of bioinformatics that the importance of IDPs in many biological processes has been recognised. ‘In this case, greater disorder in proteins allows the virus to take over the host’s machinery more easily, as it could then bind RNA, DNA and proteins more promiscuously,’ says Goh.

‘To the best of my knowledge, this is the first study that attempts to establish – and does indeed establish – a relationship between pathogenicity and the degree of intrinsic disorder in the virus,’ comments Sonia Longhi, an expert in the role of IDPs in a virological context and head of the structural disorder and molecular recognition group within the AFMB laboratory in France. She suggests that the specific interactions of these disordered proteins with host proteins should be investigated next.

‘It will be easy for anyone to come up with various new strategies for Ebola virus vaccine development based on our results,’ says Goh. ‘Furthermore, our model allows us to peer into the ways that the virus is evolving, especially during epidemics.’ He envisions other opportunities arising from these findings, including the chance to develop oncolytic viruses for cancer treatment. ‘All viruses are known to disrupt the signals of cancer cells, since they use the same signalling pathways, and viruses are already being used to treat cancer. Once we have a complete understanding of how to “defang” the Ebola virus, our study has shown us how to get the virus to multiply rapidly.’