Ebola Virus Epidemiology, Transmission, and Evolution during Seven Months in Sierra Leone

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Summary

The 2013–2015 Ebola virus disease (EVD) epidemic is caused by the Makona variant of Ebola virus (EBOV). Early in the epidemic, genome sequencing provided insights into virus evolution and transmission and offered important information for outbreak response. Here, we analyze sequences from 232 patients sampled over 7 months in Sierra Leone, along with 86 previously released genomes from earlier in the epidemic. We confirm sustained human-to-human transmission within Sierra Leone and find no evidence for import or export of EBOV across national borders after its initial introduction. Using high-depth replicate sequencing, we observe both host-to-host transmission and recurrent emergence of intrahost genetic variants. We trace the increasing impact of purifying selection in suppressing the accumulation of nonsynonymous mutations over time. Finally, we note changes in the mucin-like domain of EBOV glycoprotein that merit further investigation. These findings clarify the movement of EBOV within the region and describe viral evolution during prolonged human-to-human transmission.

Graphical Abstract

Highlights

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In Sierra Leone, transmission has primarily been within-country, not between-country
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Infectious doses are large enough for intrahost variants to transmit between hosts
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A prolonged epidemic removes deleterious mutations from the viral population
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There is preliminary evidence for human RNA editing effects on the Ebola genome

Abstract

Ebola virus genomes from 232 patients sampled over 7 months in Sierra Leone were sequenced. Transmission of intrahost genetic variants suggests a sufficiently high infectious dose during transmission. The human host may have caused direct alterations to the Ebola virus genome.

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Most cited references 25

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Time dependency of molecular rate estimates and systematic overestimation of recent divergence times.

Simon Y W Ho, Matthew J. Phillips, Alan Cooper … (2005)

Studies of molecular evolutionary rates have yielded a wide range of rate estimates for various genes and taxa. Recent studies based on population-level and pedigree data have produced remarkably high estimates of mutation rate, which strongly contrast with substitution rates inferred in phylogenetic (species-level) studies. Using Bayesian analysis with a relaxed-clock model, we estimated rates for three groups of mitochondrial data: avian protein-coding genes, primate protein-coding genes, and primate d-loop sequences. In all three cases, we found a measurable transition between the high, short-term (< 1-2 Myr) mutation rate and the low, long-term substitution rate. The relationship between the age of the calibration and the rate of change can be described by a vertically translated exponential decay curve, which may be used for correcting molecular date estimates. The phylogenetic substitution rates in mitochondria are approximately 0.5% per million years for avian protein-coding sequences and 1.5% per million years for primate protein-coding and d-loop sequences. Further analyses showed that purifying selection offers the most convincing explanation for the observed relationship between the estimated rate and the depth of the calibration. We rule out the possibility that it is a spurious result arising from sequence errors, and find it unlikely that the apparent decline in rates over time is caused by mutational saturation. Using a rate curve estimated from the d-loop data, several dates for last common ancestors were calculated: modern humans and Neandertals (354 ka; 222-705 ka), Neandertals (108 ka; 70-156 ka), and modern humans (76 ka; 47-110 ka). If the rate curve for a particular taxonomic group can be accurately estimated, it can be a useful tool for correcting divergence date estimates by taking the rate decay into account. Our results show that it is invalid to extrapolate molecular rates of change across different evolutionary timescales, which has important consequences for studies of populations, domestication, conservation genetics, and human evolution.

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Structures of protective antibodies reveal sites of vulnerability on Ebola virus.

Charles Murin, Marnie L. Fusco, Zachary A. Bornholdt … (2014)

Ebola virus (EBOV) and related filoviruses cause severe hemorrhagic fever, with up to 90% lethality, and no treatments are approved for human use. Multiple recent outbreaks of EBOV and the likelihood of future human exposure highlight the need for pre- and postexposure treatments. Monoclonal antibody (mAb) cocktails are particularly attractive candidates due to their proven postexposure efficacy in nonhuman primate models of EBOV infection. Two candidate cocktails, MB-003 and ZMAb, have been extensively evaluated in both in vitro and in vivo studies. Recently, these two therapeutics have been combined into a new cocktail named ZMapp, which showed increased efficacy and has been given compassionately to some human patients. Epitope information and mechanism of action are currently unknown for most of the component mAbs. Here we provide single-particle EM reconstructions of every mAb in the ZMapp cocktail, as well as additional antibodies from MB-003 and ZMAb. Our results illuminate key and recurring sites of vulnerability on the EBOV glycoprotein and provide a structural rationale for the efficacy of ZMapp. Interestingly, two of its components recognize overlapping epitopes and compete with each other for binding. Going forward, this work now provides a basis for strategic selection of next-generation antibody cocktails against Ebola and related viruses and a model for predicting the impact of ZMapp on potential escape mutations in ongoing or future Ebola outbreaks.

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Data sharing: Make outbreak research open access.

Nathan Yozwiak, Stephen F. Schaffner, Pardis Sabeti (2015)

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Author and article information

Contributors

Daniel J. Park

Andrew Rambaut

Pardis C. Sabeti

Journal

Journal ID (nlm-ta): Cell

Journal ID (iso-abbrev): Cell

Title: Cell

Publisher: Cell Press

ISSN (Print): 0092-8674

ISSN (Electronic): 1097-4172

Publication date PMC-release: 18 June 2015

Publication date (Print): 18 June 2015

Volume: 161

Issue: 7

Pages: 1516-1526

Affiliations

[1 ]Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA

[2 ]Institute of Evolutionary Biology, Ashworth Laboratories, University of Edinburgh, Edinburgh EH9 3FL, UK

[3 ]Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA

[4 ]Kenema Government Hospital, Kenema, Sierra Leone

[5 ]National Center for Emerging and Zoonotic Infectious Diseases and National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Mailstop-G14, Atlanta, GA 30333, USA

[6 ]Scripps Translational Science Institute, The Scripps Research Institute, 3344 N Torrey Pines Court, La Jolla, CA 92037, USA

[7 ]Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA

[8 ]US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702, USA

[9 ]Tulane University, 1430 Tulane Avenue, SL-38, New Orleans, LA 70112, USA

[10 ]DNAnexus, 1975 West El Camino Real, Suite 101, Mountain View, CA 94040, USA

[11 ]Integrated Research Facility at Fort Detrick, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, B-8200 Research Plaza, Fort Detrick, Frederick, MD 21702, USA

[12 ]Médecins Sans Frontières, Rue de l’Arbre Bénit 46, 1050 Bruxelles, Belgium

[13 ]Université Cheikh Anta Diop, BP 5005, Dakar, Sénégal

[14 ]Redeemers University Nigeria, KM 46 Lagos-Ibadan Expressway, Redemption City, Ogun State, Nigeria

[15 ]University of Sierra Leone, A.J. Momoh St, Tower Hill, Freetown, Sierra Leone

[16 ]Sierra Leone Ministry of Health and Sanitation, Youyi Building, Freetown, Sierra Leone

[17 ]University of Sydney, Johns Hopkins Drive, Camperdown NSW 2050, Australia

[18 ]Fred Hutchinson Cancer Research Center, 110 Fairview Avenue North, Seattle, WA 98109, USA

[19 ]Centre for Immunology, Infection and Evolution, University of Edinburgh, Ashworth Laboratories, Edinburgh EH9 3FL, UK

[20 ]Fogarty International Center, National Institutes of Health, 31 Center Drive, MSC 2220 Bethesda, MD 20892, USA

Author notes

[∗ ]Corresponding author dpark@ 123456broadinstitute.org

[∗∗ ]Corresponding author a.rambaut@ 123456ed.ac.uk

[∗∗∗ ]Corresponding author pardis@ 123456broadinstitute.org

[21]

Co-first author

[22]

Co-senior author

Article

Publisher ID: S0092-8674(15)00690-X

DOI: 10.1016/j.cell.2015.06.007

PMC ID: 4503805

PubMed ID: 26091036

SO-VID: 4273ba71-df19-4d71-acd5-04b1cde8b0e0

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 13 May 2015

Date revision received : 26 May 2015

Date accepted : 1 June 2015

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Ebola Virus Epidemiology, Transmission, and Evolution during Seven Months in Sierra Leone

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Summary

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Abstract

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Evolutionary Cell Biology

Most cited references 25

Time dependency of molecular rate estimates and systematic overestimation of recent divergence times.

Structures of protective antibodies reveal sites of vulnerability on Ebola virus.

Data sharing: Make outbreak research open access.

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Affiliations

Author notes

Article

History

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Cited by 131