Over the past several weeks the health news has been dominated by the outbreak of infections by Ebola virus (EBOV) in several West African nations: Guinea, Sierra Leone, Liberia, and Nigeria. A study (Gire et al., 2014) published online at the end of August and now in print by a large collaborative group based in the U.S., the U.K., or West Africa applied massively parallel sequencing of the genomes of clinical isolates of the Ebola virus primarily from Sierra Leone. The results bear on the origins of the outbreak and the transmission patterns of the responsible virus lineages and may inform future investigations pertaining to diagnostic tests, the development of vaccines, and the design of therapies based on small-molecule drugs or biologics.By way of background, the EBOV associated with the current outbreak is a negative-strand enveloped RNA virus of the family Filoviridae and the genus Ebolavirus. The species name is Zaire ebolavirus and the virus name is Ebola virus. There are four other Ebolaviruses.
A total of 99 Ebola virus genomes from 78 infected patients were sequenced. The number of sequenced genomes is greater than the number of genome donors because for some (13) patients, two or more viral DNA extraction methods were employed or viral DNA was obtained at multiple timepoints. In their analysis, the authors also included three viral genome sequences from Guinean isolates that were previously published. Key findings and inferences are briefly summarized below:
1. A substantial number of fixed nucleotide substitutions (341) differentiate the current EBOV genomes from all EBOV sequences previously described. Of these nucleotide replacements, about 10% were nonsynonymous, 50% were synonymous, and 40% were noncoding. In addition, among the sequenced EBOV genomes from the current outbreak, there were 55 single nucleotide substitutions, again including nonsynonymous, synonymous, and noncoding mutations, associated with individual infected patients. One reason that these various genomic variants might be clinically relevant is that the current EBOV sequences from Sierra Leone are sufficiently different from previous sequences that they might not be detected by several standard diagnostic assays for EBOV specifically or for filoviruses more generally.
2. The very extensive genomic coverage of the sequencing methods employed in this study also revealed genome variation within individual hosts (iSNVs). A total of 263 such intrahost single nucleotide variants were identified, the majority of which were synonymous.
3. Comparison of the viral genomes of the West African outbreak with the viral genomes from the earlier Central African outbreaks permitted the construction of EBOV phylogenetic trees that then provided important spatial and temporal insights. Based on these analyses, the authors concluded that the virus responsible for the current epidemic originated in Central Africa and probably within the past ten years.
4. They also interpreted these results to suggest that the three most recent EBOV outbreaks were the results of three independent transmissions from natural animal hosts to humans. In the current outbreak, the evidence suggests that after a single animal-to-human transmission in late February of this year, human-to-human transmission accounts for the continuing incidence of infection. The authors also suggest that two genetically distinguishable viruses from Guinea crossed into Sierra Leone in late April of 2014.
5. The patterns of EBOV genome variation within and between hosts suggest that human-to-human transmission can involve two or more viral haplotypes (i.e. groups of sequence variations at different genomic positions).
6. During outbreaks, the proportion of mutations that are nonsynonymous appears to be greater than it is between outbreaks. Such patterns of genomic variation are also consistent with a measure of purifying selection. Additional studies addressing the phenotypic effects of individual mutations will be necessary to determine which of the new substitutions influence virulence or transmissibility.
I do not believe it is clear if the viruses in Sierra Leone and Guinea are substantially different in virulence or transmissibility in comparison to the virus lineages associated with earlier outbreaks. The greater spread and somewhat lower (if still frighteningly high) case fatality rate of the current outbreak may be caused in whole or in part by factors external to the virus, such as host population density and modestly more effective medical care in some currently affected areas than in the remote villages primarily affected in earlier outbreaks.
In a just published New York Times op-ed, Michael Osterholm, the director of the Center for Infectious Disease Research and Policy at the University of Minnesota, raises two outbreak-related concerns in addition to those already apparent. First, if virus were to spread to one of the “megacities” in countries with modest health care infrastructures, the scale of the outbreak could be massively enlarged. Second, if the virus were to evolve so that transmission became possible through infected aerosols, infection control would become even more difficult and expensive and the pace of spread would likely increase.
In this context, a particularly relevant point made by Osterholm is that the current outbreak has involved by far the most human-to-human transmission events of any known EBOV outbreak. Consequently, the opportunities for the sort of mutation about which Osterholm expresses concern are markedly increased. Spread of EBOV to a large densely populated city with limited health care resources could similarly increase the likelihood of an evolutionary trajectory leading to respiratory transmission. For these and other reasons, Osterholm and others, such as Pardis Sabeti (New York Times, 2014), a senior author on the new study in Science, urge a rapid, coordinated, and properly scaled international response to end the epidemic as soon as practicable.
Gire SK, Goba A, Andersen KG, Sealfon RG, it appears that there are also Park DJ … Sabeti PC. Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. Science 2014 345(6202):1369-1372, doi: 10.1126/science.1259657, published online August 28, 2014.
Osterholm MT. What we’re afraid to say about ebola. New York Times, September 11, 2014. http://www.nytimes.com/2014/09/12/opinion/what-were-afraid-to-say-about-ebola.html?ref=opinion (last accessed on 9/12/14)
Sabeti P. Studying Ebola, then dying from it. New York Times, September 7, 2014. http://www.nytimes.com/2014/09/07/opinion/sunday/studying-ebola-then-dying-from-it.html?ref=opinion
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