RT Journal Article
SR Electronic
T1 Hepatitis C Virus Infects and Perturbs Liver Stem Cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.10.26.465357
DO 10.1101/2021.10.26.465357
A1 Nathan L Meyers
A1 Tal Ashuach
A1 Danielle E Lyons
A1 Camille R Simoneau
A1 Ann L Erickson
A1 Mehdi Bouhaddou
A1 Thong T. Nguyen
A1 Mir M Khalid
A1 Taha Y Taha
A1 Vaishaali Natarajan
A1 Jody L Baron
A1 Norma Neff
A1 Fabio Zanini
A1 Tokameh Mahmoud
A1 Stephen R Quake
A1 Nevan J Krogan
A1 Stewart Cooper
A1 Todd C McDevitt
A1 Nir Yosef
A1 Melanie Ott
YR 2021
UL http://biorxiv.org/content/early/2021/10/26/2021.10.26.465357.abstract
AB Hepatitis C virus (HCV) is the leading cause of death from liver disease. How HCV infection causes lasting liver damage and increases cancer risk beyond viral clearance remains unclear. 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 extensive 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 adds a pathogenesis factor – infection of liver stem cells – to the biology of HCV infection that explains persistent liver damage and enhanced cancer risk through an altered stem cell state.Competing Interest StatementThe authors have declared no competing interest.