Out of the Woods: Ebola as a Zoonotic Viral Disease

Genomics Revolution

Genomic Revolution

Guest Hosts: Alexus Acton & Rachna Prasad

Episode 51: Ebola

Script:

Rachna: Welcome to Genomics Revolution. This is Alexus Acton and Rachna Prasad from the 2020 Hiram College Genetics course hosting this episode on the Zaire Ebolavirus. This virus causes the disease ebola that originated from human animal contact, most likely from a bat (1). The Ebola Virus Disease, or EVD for short, was first discovered in 1976 with 2 consecutive outbreaks of fatal hemorrhagic fever in Central Africa. The first outbreak was in the Democratic Republic of Congo, which was formerly called Zaire, in à village near the Ebola river, which accounted for nearly 2700 deaths. The second outbreak was in South Sudan. Originally scientists believed it was spread by à single infected person travelling between the two areas, but it was later discovered they were two genetically distinct viruses - the Zaire ebolavirus and the Sudan ebolavirus.(4) The most recent, and familiar Ebola outbreak occurred in 2014-2016, originating in Southeastern Guinea. It rapidly spread to urban populations within weeks, and soon turned into à global epidemic. (4)

Lexi: With this virus going many months without detection we should care about knowing about this virus because the human-human transmission chain was growing exponentially. Before the World health Organization declared it an outbreak, it had already spread over country borders infecting thousands of people (1). Ebola virus is a negative- sense single strand RNA ((-)ssRNA) that has a 19 kilobase genome (1). There are several encoded proteins from EVD which are nucleoprotein (NP), viral proteins (VP) as well as RNA polymerase (L), and Glycoprotein (GP) (2). VP24 is a membrane associated protein, VP30 and VP35 are polymerase matrix proteins, and VP40 is a matrix protein (2). VP40 is the primary EVD matrix protein and regulated assembly and progress of infectious particles (2). It assembles on the inner leaflet of the plasma membrane in human cells to regulate viral budding. Each of these genes encodes for a single protein product with the exception of GP. Gp encodes three proteins of different sizes with a full length of 676 residues. Glycoprotein 1 and 2, mediates viral-host cell attachment and fusion (2). Like other RNA viruses ebola quickly generates mutations through error prone replication. The various glycoproteins are produced from frameshift as a result of mRNA editing (1).

Rachna: Ebolavirus belongs to à group of viruses called filoviruses. A phylogenetic analysis revealed that the Sudan Ebola virus diverged early from the other strains, showing that the Bundibugyo and Tai Forest were closely related to Zaire Ebola Virus (2). EBOV is à single stranded RNA virus. This gives it a higher likelihood of acquiring meaningful genetic adaptations and evolving into different strains, when compared to other DNA viruses. (5) À 2017 study, by Tao Li et al., conducted on 514 different EBOV genome sequences from patients with confirmed EVD cases showed that 11 different lineages of EBOV arose from one outbreak in Sierra Leone alone. It also showed that different lineages of EBOV had different fatality rates and certain strains with specific SNPs correlated with higher fatality rates. Variation in nucleotide sequences can help target each Ebolavirus strain from one another, ultimately leading to better diagnosis and therapeutics. This is important to note as the divergence of diseases from other common viruses could potentially be headway in targeting vaccines and treatments to those infected.

Lexi: Evidence demonstrates cooperative dimeric binding of double stranded RNA by ebolavirus VP35. The C-terminal domain of viral protein 35 dimerizes upon binding to double stranded RNA, showing coppertivity (3). Reston ebolavirus is named to show where it was derived from, which has previously been shown to be critical for RNA binding, but is also important for VP35 dimeric interface binding (3). These researches mutated R312/301 which likely abolished dsRNA binding which disrupted the formation of the viral protein dimer leaving it in unstable formation (3). This is important as the binding mechanism permits the ebola virus from avoiding the innate immune response and enhancing harmfulness to human cells. (3). This alone can help researchers target the structure based conformational states or protein targeting drugs for drug development and biodefense mechanisms.

Rachna: One study showed that multi sequence alignment generated several conserved sequences from each protein mentioned above. Using an Ebola strain from 1976 and a recent strain of 2014, the two sequences were 100% identical (6). The conservation allowed for detection of B and T cell epitopes which covered between 25.37 and 61.51% of the population (6). B cell epitope is the portion of the antigen which interacts with B lymphocytes to trigger immune responses (6). The importance of this is to understand the efficacy in eliciting immunity through humoral and cell-mediated immune responses. T cell immune response usually promises long lasting immunity, and here the prediction of T and B cell epitopes provides two alternative but effective immune response mechanisms.

Lexi: Thank you for tuning in on this podcast of Genomics Revolution. We hope you enjoyed your time and learned something new about Ebola.

References:

1. Holmes, Edward C., et al. “The Evolution of Ebola Virus: Insights from the 2013–2016 Epidemic.” Nature, vol. 538, no. 7624, 13 Oct. 2016, pp. 193–200., doi:10.1038/nature19790.

2. Jun, Se-Ran et al. “Ebolavirus comparative genomics.” FEMS microbiology reviews vol. 39,5 (2015): 764-78. doi:10.1093/femsre/fuv031

3. Kimberlin, C. R., et al. “Ebolavirus VP35 Uses a Bimodal Strategy to Bind DsRNA for Innate Immune Suppression.” Proceedings of the National Academy of Sciences, vol. 107, no. 1, 14 Sept. 2009, pp. 314–319., doi:10.1073/pnas.0910547107.

4. Li T, Yao HW, Liu D, et al. Mapping the clinical outcomes and genetic evolution of Ebola virus in Sierra Leone. JCI Insight. 2017;2(15):e88333. Published 2017 Aug 3. doi:10.1172/jci.insight.88333

5. Regnery, RL., Johnson, KM., and Kiley, MP. Virion nucleic acid of Ebola virus. J. Virol. 1980; 36(2): 465-469.

6. Yasmin, T., and A. H. M. Nurun Nabi. “B And T Cell Epitope-Based Peptides Predicted from Evolutionarily Conserved and Whole Protein Sequences of Ebola Virus as Vaccine Targets.” Scandinavian Journal of Immunology, vol. 83, no. 5, 2016, pp. 321–337., doi:10.1111/sji.12425.