A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease

Michael L. Washburn, Moses T. Bility, Liguo Zhang, Grigoriy I. Kovalev, Adam Buntzman, Jeffrey A Frelinger, Walter Barry, Alexander Ploss, Charles M. Rice, Lishan Su

Research output: Contribution to journalArticle

196 Citations (Scopus)

Abstract

Background & Aims: Studies of hepatitis C virus (HCV) infection, immunopathogenesis, and resulting liver diseases have been hampered by the lack of a small animal model. We developed humanized mice with human immune system and liver tissues to improve the studies of hepatitis C virus pathogenesis and treatment. Methods: To promote engraftment of human hepatocytes, we expressed a fusion protein of the FK506 binding protein (FKBP) and caspase 8 under control of the albumin promoter (AFC8), which induces liver cell death, in Balb/C Rag2-/- γC-null mice. Cotransplantation of human CD34 + human hematopoietic stem cells (HSC) and hepatocyte progenitors into the transgenic mice led to efficient engraftment of human leukocytes and hepatocytes. We then infected these humanized mice (AFC8-hu HSC/Hep) with primary HCV isolates and studied HCV-induced immune responses and liver diseases. Results: AFC8-hu HSC/Hep mice supported HCV infection in the liver and generated a human immune T-cell response against HCV. HCV infection induced liver inflammation, hepatitis, and fibrosis, which correlated with activation of stellate cells and expression of human fibrogenic genes. Conclusions: AFC8-hu HSC/Hep mice are a useful model of HCV infection, the immune response, and liver disease because they contain human immune system and liver cells. These mice become infected with HCV, generate a specific immune response against the virus, and develop liver diseases that include hepatitis and fibrosis. This model might also be used to develop therapeutics for HCV infection.

Original languageEnglish (US)
Pages (from-to)1334-1344
Number of pages11
JournalGastroenterology
Volume140
Issue number4
DOIs
StatePublished - Apr 2011
Externally publishedYes

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Immune System Diseases
Virus Diseases
Hepacivirus
Liver Diseases
Hematopoietic Stem Cells
Liver
Hepatocytes
Hepatitis
Immune System
Fibrosis
Tacrolimus Binding Proteins
Caspase 8
Transgenic Mice
Albumins
Leukocytes
Cell Death
Animal Models
Viruses
Inflammation
T-Lymphocytes

Keywords

  • Animal Model of Hepatitis
  • Fibrosis
  • Human Immunology
  • Virology

ASJC Scopus subject areas

  • Gastroenterology

Cite this

A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. / Washburn, Michael L.; Bility, Moses T.; Zhang, Liguo; Kovalev, Grigoriy I.; Buntzman, Adam; Frelinger, Jeffrey A; Barry, Walter; Ploss, Alexander; Rice, Charles M.; Su, Lishan.

In: Gastroenterology, Vol. 140, No. 4, 04.2011, p. 1334-1344.

Research output: Contribution to journalArticle

Washburn, ML, Bility, MT, Zhang, L, Kovalev, GI, Buntzman, A, Frelinger, JA, Barry, W, Ploss, A, Rice, CM & Su, L 2011, 'A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease', Gastroenterology, vol. 140, no. 4, pp. 1334-1344. https://doi.org/10.1053/j.gastro.2011.01.001
Washburn, Michael L. ; Bility, Moses T. ; Zhang, Liguo ; Kovalev, Grigoriy I. ; Buntzman, Adam ; Frelinger, Jeffrey A ; Barry, Walter ; Ploss, Alexander ; Rice, Charles M. ; Su, Lishan. / A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. In: Gastroenterology. 2011 ; Vol. 140, No. 4. pp. 1334-1344.
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AU - Buntzman, Adam

AU - Frelinger, Jeffrey A

AU - Barry, Walter

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AU - Rice, Charles M.

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AB - Background & Aims: Studies of hepatitis C virus (HCV) infection, immunopathogenesis, and resulting liver diseases have been hampered by the lack of a small animal model. We developed humanized mice with human immune system and liver tissues to improve the studies of hepatitis C virus pathogenesis and treatment. Methods: To promote engraftment of human hepatocytes, we expressed a fusion protein of the FK506 binding protein (FKBP) and caspase 8 under control of the albumin promoter (AFC8), which induces liver cell death, in Balb/C Rag2-/- γC-null mice. Cotransplantation of human CD34 + human hematopoietic stem cells (HSC) and hepatocyte progenitors into the transgenic mice led to efficient engraftment of human leukocytes and hepatocytes. We then infected these humanized mice (AFC8-hu HSC/Hep) with primary HCV isolates and studied HCV-induced immune responses and liver diseases. Results: AFC8-hu HSC/Hep mice supported HCV infection in the liver and generated a human immune T-cell response against HCV. HCV infection induced liver inflammation, hepatitis, and fibrosis, which correlated with activation of stellate cells and expression of human fibrogenic genes. Conclusions: AFC8-hu HSC/Hep mice are a useful model of HCV infection, the immune response, and liver disease because they contain human immune system and liver cells. These mice become infected with HCV, generate a specific immune response against the virus, and develop liver diseases that include hepatitis and fibrosis. This model might also be used to develop therapeutics for HCV infection.

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