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A new approach for understanding Ebola virus pathogenesis

Image
Researchers in the Sabeti Lab prepare a genomics experiment. (Credit: Oliver Douliery, Broad Institute)

Overview | Project description | Project tasks | Additional reading | Related links

Image: Researchers in the Sabeti Lab prepare a genomics experiment. (Credit: Oliver Douliery, via Flickr)

Performer: Broad Institute of MIT and Harvard
Project leader: Professor Pardis C. Sabeti, M.D., D. Phil.
Contract value: $940,000
Project dates: November 2018 to October 2020

Overview

Infection with Ebola virus results in a series of complex events within the body that lead to disease—including immune suppression and organ-specific damage. In addition, how the Ebola virus evolves within the body is suspected to play a key role in Ebola virus disease progression.

The interaction among these factors and how they contribute to the overall effect the Ebola virus has on the body and the outcomes of infection remains poorly understood. This is in part because the Ebola virus spreads rapidly throughout the body, simultaneously affecting multiple organs, resulting in many changes in the body’s gene expression. These changes, as well as the Ebola virus evolution during infection and its effects on disease progression, are difficult to track and analyze.

Acquiring a deeper understanding of the biological mechanisms that contribute to Ebola virus disease is critical to developing medical countermeasures (MCMs) to prevent and treat Ebola virus disease.

Project description

In September 2018, FDA awarded a two-year contract to the Broad Institute to conduct the largest Ebola virus and host gene expression (i.e., transcriptomics) study to date. Researchers at the Broad Institute will use the latest sequencing technologies, including single-cell sequencing methods, to assess how Ebola virus evolves and spreads within the body. They also aim to identify mechanisms and biological pathways that are altered in immune cells and tissues throughout the body during infection. This work will inform the natural history of Ebola virus disease in humans and help characterize nonclinical models necessary for testing Ebola MCMs.

The contract also includes two option periods for potential Lassa virus research in future fiscal years.

This project builds on previous and ongoing research conducted by the National Institutes of Health (NIH) Integrated Research Facility (IRF) leveraging samples and knowledge developed from over more than a decade of collaborative Ebola and Lassa virus research between Broad Institute researchers, the NIH IRF, and the Department of Defense.

Project tasks

Using samples from previous NIH IRF research, the Broad Institute will:

  • Study Ebola variation, evolution, host response, and circulation between tissues by extracting RNA from a total of 20 sample types; measuring by spectrophotometry; performing PCR to extract sequencing-quality RNA; quantifying viral load; preparing 4 RNA-sequence libraries of 150 samples each; and sequencing each batch, generating a minimum of 5 million reads/pairs. They will then study and compare the sequences using various techniques.
  • Use novel, portable, and low-cost Seq-Well technology to quantify single-cell gene expression changes between infected and non-infected peripheral blood mononuclear cells (PBMCs), to determine which cells are responsible for which changes in gene expression and identify shifts in immune cell populations over time.
  • Perform total RNA sequencing on a wide variety of tissue samples collected at all stages of Ebola virus disease, to better understand how different tissues respond to Ebola infection and survey changes in host gene expression.
  • Optimize single-cell sequencing for Lassa virusand other viral hemorrhagic fevers, to enable future studies needed for MCM development for these pathogens.

This work will help fill significant gaps in the scientific community’s understanding of how Ebola virus disease progresses at the molecular level, which will help identify biological pathways and mechanisms that could be useful biomarkers to assess the efficacy of MCMs, or advance development of potential therapeutics. In addition, the models and methods established will enable future research important to MCM development for viral hemorrhagic fevers, including evaluation of investigational MCMs such as vaccines and therapeutics.

This project was funded through the MCMi Regulatory Science Extramural Research program

Additional reading

Gire, Stephen K., Augustine Goba, Kristian G. Andersen, Rachel S. G. Sealfon, Daniel J. Park, Lansana Kanneh, Simbirie Jalloh, et al. 2014. “Genomic Surveillance Elucidates Ebola Virus Origin and Transmission during the 2014 Outbreak.” Science 345 (6202): 1369–72. doi: 10.1126/science.1259657

Gierahn, Todd M., Wadsworth II, Marc H., Hughes, Travis K., Bryson, Bryan D., Butler, Andrew., Satija, Rahul., Fortune, Sarah., et al. 2017. “Seq-Well: portable, low-cost RNA sequencing of single cells at high throughput.” Nature Methods 14, 395-398 doi: 10.1038/nmeth.4179

Caballero, Ignacio S., Anna N. Honko, Stephen K. Gire, Sarah M. Winnicki, Marta Melé, Chiara Gerhardinger, Aaron E. Lin, et al. 2016. “In Vivo Ebola Virus Infection Leads to a Strong Innate Response in Circulating Immune Cells.” BMC Genomics 17 (September): 707. doi: 10.1186/s12864-016-3060-0

Park, Daniel J., Gytis Dudas, Shirlee Wohl, Augustine Goba, Shannon L. M. Whitmer, Kristian G. Andersen, Rachel S. Sealfon, et al. 2015. “Ebola Virus Epidemiology, Transmission, and Evolution during Seven Months in Sierra Leone.” Cell 161 (7): 1516–26. doi: 10.1016/j.cell.2015.06.007

Rubins, Kathleen H., Lisa E. Hensley, Victoria Wahl-Jensen, Kathleen M. Daddario DiCaprio, Howard A. Young, Douglas S. Reed, Peter B. Jahrling, Patrick O. Brown, David A. Relman, and Thomas W. Geisbert. 2007. “The Temporal Program of Peripheral Blood Gene Expression in the Response of Nonhuman Primates to Ebola Hemorrhagic Fever.” Genome Biology 8 (8): R174. doi:  10.1186/gb-2007-8-8-r174

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