Hepatitis C virus infects and perturbs liver stem cells

NL Meyers; T Ashuach; DE Lyons; MM Khalid; CR Simoneau; AL Erickson; M Bouhaddou; TT Nguyen; GR Kumar; TY Taha; V Natarajan; JL Baron; N Neff; F Zanini; T Mahmoudi; SR Quake; NJ Krogan; S Cooper; TC Mcdevitt; N Yosef; M Ott

doi:10.1128/mbio.01318-23

Hepatitis C virus infects and perturbs liver stem cells

NL Meyers, T Ashuach, DE Lyons, MM Khalid, CR Simoneau, AL Erickson, M Bouhaddou, TT Nguyen, GR Kumar, TY Taha, V Natarajan, JL Baron, N Neff, F Zanini, T Mahmoudi, SR Quake, NJ Krogan, S Cooper, TC Mcdevitt, N Yosef^*M Ott^*

^*Corresponding author for this work

Pathology

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Abstract

Hepatitis 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.

Original language	English
Article number	0131823
Number of pages	21
Journal	mBio
Volume	14
Issue number	6
Early online date	8 Nov 2023
DOIs	https://doi.org/10.1128/mbio.01318-23
Publication status	Published - Dec 2023

Bibliographical note

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Copyright © 2023 Meyers et al.

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Meyers, NL., Ashuach, T., Lyons, DE., Khalid, MM., Simoneau, CR., Erickson, AL., Bouhaddou, M., Nguyen, TT., Kumar, GR., Taha, TY., Natarajan, V., Baron, JL., Neff, N., Zanini, F., Mahmoudi, T., Quake, SR., Krogan, NJ., Cooper, S., Mcdevitt, TC., ... Ott, M. (2023). Hepatitis C virus infects and perturbs liver stem cells. mBio, 14(6), Article 0131823. https://doi.org/10.1128/mbio.01318-23

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title = "Hepatitis C virus infects and perturbs liver stem cells",

abstract = "Hepatitis 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.",

author = "NL Meyers and T Ashuach and DE Lyons and MM Khalid and CR Simoneau and AL Erickson and M Bouhaddou and TT Nguyen and GR Kumar and TY Taha and V Natarajan and JL Baron and N Neff and F Zanini and T Mahmoudi and SR Quake and NJ Krogan and S Cooper and TC Mcdevitt and N Yosef and M Ott",

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Meyers, NL, Ashuach, T, Lyons, DE, Khalid, MM, Simoneau, CR, Erickson, AL, Bouhaddou, M, Nguyen, TT, Kumar, GR, Taha, TY, Natarajan, V, Baron, JL, Neff, N, Zanini, F, Mahmoudi, T, Quake, SR, Krogan, NJ, Cooper, S, Mcdevitt, TC, Yosef, N & Ott, M 2023, 'Hepatitis C virus infects and perturbs liver stem cells', mBio, vol. 14, no. 6, 0131823. https://doi.org/10.1128/mbio.01318-23

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T1 - Hepatitis C virus infects and perturbs liver stem cells

AU - Meyers, NL

AU - Ashuach, T

AU - Lyons, DE

AU - Khalid, MM

AU - Simoneau, CR

AU - Erickson, AL

AU - Bouhaddou, M

AU - Nguyen, TT

AU - Kumar, GR

AU - Taha, TY

AU - Natarajan, V

AU - Baron, JL

AU - Neff, N

AU - Zanini, F

AU - Mahmoudi, T

AU - Quake, SR

AU - Krogan, NJ

AU - Cooper, S

AU - Mcdevitt, TC

AU - Yosef, N

AU - Ott, M

PY - 2023/12

Y1 - 2023/12

N2 - Hepatitis 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.

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 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.

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SN - 2161-2129

VL - 14

JO - mBio

JF - mBio

IS - 6

M1 - 0131823

ER -

Hepatitis C virus infects and perturbs liver stem cells

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