Hepatitis C virus infects and perturbs liver stem cells
Nathan L. Meyers,
Tal Ashuach,
Danielle E. Lyons,
Mir M. Khalid,
Camille R. Simoneau,
Ann L. Erickson,
Mehdi Bouhaddou,
Thong T. Nguyen,
G. Renuka Kumar,
Taha Y. Taha,
Vaishaali Natarajan,
Jody L. Baron,
Norma Neff,
Fabio Zanini,
Tokameh Mahmoudi,
Stephen R. Quake,
Nevan J. Krogan,
Stewart Cooper,
Todd C. McDevitt,
Nir Yosef,
Melanie Ott
Affiliations
Nathan L. Meyers
Gladstone Institute of Virology, San Francisco, California, USA
Tal Ashuach
Department of Electrical Engineering and Computer Science and Center for Computational Biology, University of California Berkeley, Berkeley, California, USA
Danielle E. Lyons
Gladstone Institute of Virology, San Francisco, California, USA
Mir M. Khalid
Gladstone Institute of Virology, San Francisco, California, USA
Camille R. Simoneau
Gladstone Institute of Virology, San Francisco, California, USA
Ann L. Erickson
California Pacific Medical Center Research Institute, San Francisco, California, USA
Mehdi Bouhaddou
Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
Thong T. Nguyen
Gladstone Institute of Virology, San Francisco, California, USA
G. Renuka Kumar
Gladstone Institute of Virology, San Francisco, California, USA
Taha Y. Taha
Gladstone Institute of Virology, San Francisco, California, USA
Vaishaali Natarajan
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA
Jody L. Baron
Department of Medicine, University of California San Francisco, San Francisco, California, USA
Norma Neff
Chan Zuckerburg Biohub, San Francisco, California, USA
Fabio Zanini
Department of Bioengineering, Stanford University, Stanford, California, USA
Tokameh Mahmoudi
Department of Biochemistry, Erasmus University Medical Center, Rotterdam, the Netherlands
Stephen R. Quake
Chan Zuckerburg Biohub, San Francisco, California, USA
Nevan J. Krogan
Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
Stewart Cooper
California Pacific Medical Center Research Institute, San Francisco, California, USA
Todd C. McDevitt
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA
Nir Yosef
Department of Electrical Engineering and Computer Science and Center for Computational Biology, University of California Berkeley, Berkeley, California, USA
Melanie Ott
Gladstone Institute of Virology, San Francisco, California, USA
ABSTRACTHepatitis C virus (HCV) is the leading cause of death from liver disease. How HCV infection causes lasting liver damage and increases cancer risk remains unclear. Here, we identify bipotent liver stem cells as novel targets for HCV infection, and their erroneous differentiation as the potential cause of impaired liver regeneration and cancer development. We show 3D organoids generated from liver stem cells from actively HCV-infected individuals carry replicating virus and maintain low-grade infection over months. Organoids can be infected with a primary HCV isolate. Virus-inclusive single-cell RNA sequencing uncovered transcriptional reprogramming in HCV+ cells supporting hepatocytic differentiation, cancer stem cell development, and viral replication while stem cell proliferation and interferon signaling are disrupted. Our data add a new pathogenesis mechanism—infection of liver stem cells—to the biology of HCV infection that may explain progressive liver damage and enhanced cancer risk through an altered stem cell state.IMPORTANCEThe hepatitis C virus (HCV) causes liver disease, affecting millions. Even though we have effective antivirals that cure HCV, they cannot stop terminal liver disease. We used an adult stem cell-derived liver organoid system to understand how HCV infection leads to the progression of terminal liver disease. Here, we show that HCV maintains low-grade infections in liver organoids for the first time. HCV infection in liver organoids leads to transcriptional reprogramming causing cancer cell development and altered immune response. Our finding shows how HCV infection in liver organoids mimics HCV infection and patient pathogenesis. These results reveal that HCV infection in liver organoids contributes to liver disease progression.
