Ebola virus infection induces a delayed type I IFN response in bystander cells and the shutdown of key liver genes in human iPSC-derived hepatocytes

Whitney A Scoon; Liliana Mancio-Silva; Ellen L Suder; Carlos Villacorta-Martin; Jonathan Lindstrom-Vautrin; John G Bernbaum; Steve Mazur; Reed F Johnson; Judith Olejnik; Elizabeth Y Flores; Aditya Mithal; Feiya Wang; Adam J Hume; Joseph E Kaserman; Sandra March-Riera; Andrew A Wilson; Sangeeta N Bhatia; Elke Mühlberger; Gustavo Mostoslavsky

doi:10.1016/j.stemcr.2022.08.003

Ebola virus infection induces a delayed type I IFN response in bystander cells and the shutdown of key liver genes in human iPSC-derived hepatocytes

Stem Cell Reports. 2022 Oct 11;17(10):2286-2302. doi: 10.1016/j.stemcr.2022.08.003. Epub 2022 Sep 8.

Authors

Whitney A Scoon¹, Liliana Mancio-Silva², Ellen L Suder³, Carlos Villacorta-Martin⁴, Jonathan Lindstrom-Vautrin⁴, John G Bernbaum⁵, Steve Mazur⁵, Reed F Johnson⁶, Judith Olejnik³, Elizabeth Y Flores¹, Aditya Mithal⁷, Feiya Wang⁴, Adam J Hume³, Joseph E Kaserman⁸, Sandra March-Riera², Andrew A Wilson⁸, Sangeeta N Bhatia⁹, Elke Mühlberger¹⁰, Gustavo Mostoslavsky¹¹

Affiliations

¹ Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, 670 Albany Street, Suite 209, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, 620 Albany Street, Boston, MA 02118, USA; Department of Microbiology, Boston University School of Medicine, 620 Albany Street, Boston, MA 02118, USA.
² Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, MA 02139, USA.
³ National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, 620 Albany Street, Boston, MA 02118, USA; Department of Microbiology, Boston University School of Medicine, 620 Albany Street, Boston, MA 02118, USA.
⁴ Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, 670 Albany Street, Suite 209, Boston, MA 02118, USA.
⁵ Integrated Research Facility, Division of Clinical Research, National Institute for Allergy and Infectious Disease, National Institutes of Health, Frederick, MD 21702, USA.
⁶ Integrated Research Facility, Division of Clinical Research, National Institute for Allergy and Infectious Disease, National Institutes of Health, Frederick, MD 21702, USA; Emerging Viral Pathogens Section, Laboratory of Immunoregulation, Division of Intramural Research, National Institute for Allergy and Infectious Disease, National Institutes of Health, Frederick, MD 21702, USA.
⁷ Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, 670 Albany Street, Suite 209, Boston, MA 02118, USA; Department of Microbiology, Boston University School of Medicine, 620 Albany Street, Boston, MA 02118, USA.
⁸ Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, 670 Albany Street, Suite 209, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
⁹ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, MA 02139, USA; Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA; Broad Institute, Cambridge, MA 02139, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
¹⁰ National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, 620 Albany Street, Boston, MA 02118, USA; Department of Microbiology, Boston University School of Medicine, 620 Albany Street, Boston, MA 02118, USA. Electronic address: muehlber@bu.edu.
¹¹ Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, 670 Albany Street, Suite 209, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, 620 Albany Street, Boston, MA 02118, USA; Department of Microbiology, Boston University School of Medicine, 620 Albany Street, Boston, MA 02118, USA; Section of Gastroenterology, Department of Medicine, Boston University School of Medicine, 670 Albany Street, Suite 209, Boston, MA 02118, USA. Electronic address: gmostosl@bu.edu.

Abstract

Liver damage and an exacerbated inflammatory response are hallmarks of Ebola virus (EBOV) infection. Little is known about the intrinsic response to infection in human hepatocytes and their contribution to inflammation. Here, we present an induced pluripotent stem cell (iPSC)-derived hepatocyte-like cell (HLC) platform to define the hepato-intrinsic response to EBOV infection. We used this platform to show robust EBOV infection, with characteristic ultrastructural changes and evidence for viral replication. Transcriptomics analysis revealed a delayed response with minimal early transcriptomic changes, followed by a general downregulation of hepatic function and upregulation of interferon signaling, providing a potential mechanism by which hepatocytes participate in disease severity and liver damage. Using RNA-fluorescence in situ hybridization (FISH), we showed that IFNB1 and CXCL10 were mainly expressed in non-infected bystander cells. We did not observe an inflammatory signature during infection. In conclusion, iPSC-HLCs are an immune competent platform to study responses to EBOV infection.

Keywords: Ebola virus host response; Ebola virus infection; downregulation key liver genes; iPSC-hepatocytes.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Ebolavirus* / physiology
Hemorrhagic Fever, Ebola*
Hepatocytes
Humans
In Situ Hybridization, Fluorescence
Induced Pluripotent Stem Cells*
Interferons
Liver
RNA

Substances

RNA
Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding