Natural history of Ebola virus disease in rhesus monkeys shows viral variant emergence dynamics and tissue-specific host responses

Erica Normandin; Sergio Triana; Siddharth S Raju; Tammy C T Lan; Kim Lagerborg; Melissa Rudy; Gordon C Adams; Katherine C DeRuff; James Logue; David Liu; Daniel Strebinger; Arya Rao; Katelyn S Messer; Molly Sacks; Ricky D Adams; Krisztina Janosko; Dylan Kotliar; Rickey Shah; Ian Crozier; John L Rinn; Marta Melé; Anna N Honko; Feng Zhang; Mehrtash Babadi; Jeremy Luban; Richard S Bennett; Alex K Shalek; Nikolaos Barkas; Aaron E Lin; Lisa E Hensley; Pardis C Sabeti; Katherine J Siddle

doi:10.1016/j.xgen.2023.100440

Natural history of Ebola virus disease in rhesus monkeys shows viral variant emergence dynamics and tissue-specific host responses

Cell Genom. 2023 Nov 21;3(12):100440. doi: 10.1016/j.xgen.2023.100440. eCollection 2023 Dec 13.

Authors

Erica Normandin^{1

2}, Sergio Triana^{1

3

4

5}, Siddharth S Raju^{1

2}, Tammy C T Lan^{1

6}, Kim Lagerborg^{1

7}, Melissa Rudy¹, Gordon C Adams^{1

8}, Katherine C DeRuff¹, James Logue⁹, David Liu⁹, Daniel Strebinger^{1

10

11

12

13}, Arya Rao^{14

15}, Katelyn S Messer¹, Molly Sacks¹, Ricky D Adams⁹, Krisztina Janosko⁹, Dylan Kotliar^{1

2

3}, Rickey Shah¹, Ian Crozier¹⁶, John L Rinn¹⁷, Marta Melé¹⁸, Anna N Honko^{9

19}, Feng Zhang^{1

10

11

12

13}, Mehrtash Babadi¹, Jeremy Luban^{1

5

20}, Richard S Bennett⁹, Alex K Shalek^{1

3

4

5}, Nikolaos Barkas¹, Aaron E Lin^{1

21

22

23}, Lisa E Hensley⁹, Pardis C Sabeti^{1

10

24

25}, Katherine J Siddle^{1

26}

Affiliations

¹ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
² Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
³ Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁴ Department of Chemistry, Institute for Medical Engineering and Sciences (IMES), and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02142, USA.
⁵ Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA 02139, USA.
⁶ Department of Molecular and Cellular Biology, Harvard University, Boston, MA, USA.
⁷ Harvard Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
⁸ Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA.
¹⁰ Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA.
¹¹ McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹² Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹³ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁴ Columbia University, New York, NY, USA.
¹⁵ Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA.
¹⁶ Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
¹⁷ Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80303, USA.
¹⁸ Life Sciences Department, Barcelona Supercomputing Center, 08034 Barcelona, Catalonia, Spain.
¹⁹ National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02118, USA.
²⁰ Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
²¹ Harvard Program in Virology, Harvard Medical School, Boston, MA 02115, USA.
²² Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
²³ Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
²⁴ Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.
²⁵ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
²⁶ Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.

Abstract

Ebola virus (EBOV) causes Ebola virus disease (EVD), marked by severe hemorrhagic fever; however, the mechanisms underlying the disease remain unclear. To assess the molecular basis of EVD across time, we performed RNA sequencing on 17 tissues from a natural history study of 21 rhesus monkeys, developing new methods to characterize host-pathogen dynamics. We identified alterations in host gene expression with previously unknown tissue-specific changes, including downregulation of genes related to tissue connectivity. EBOV was widely disseminated throughout the body; using a new, broadly applicable deconvolution method, we found that viral load correlated with increased monocyte presence. Patterns of viral variation between tissues differentiated primary infections from compartmentalized infections, and several variants impacted viral fitness in a EBOV/Kikwit minigenome system, suggesting that functionally significant variants can emerge during early infection. This comprehensive portrait of host-pathogen dynamics in EVD illuminates new features of pathogenesis and establishes resources to study other emerging pathogens.

Keywords: Ebola virus; Ebola virus disease; deconvolution; hemorrhagic fevers; host-virus interactions; minigenome; non-human primates; transcriptomics; viral variants.

MeSH terms

Animals
Ebolavirus* / genetics
Hemorrhagic Fever, Ebola* / pathology
Hemorrhagic Fevers, Viral*
Macaca mulatta

Abstract

MeSH terms

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