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Cited by 227Hepatitis B Virus StudiesLiver physiology and pathologyHepatitis C virus research

Hepatitis B Virus Infection and Immunopathogenesis in a Humanized Mouse Model: Induction of Human-Specific Liver Fibrosis and M2-Like Macrophages

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Bility, Moses T., Cheng, Liang, Zhang, Zheng, Luan, Yan, Li, Feng, Chi, Liqun, Zhang, Liguo, Tu, Zhengkun +5 more·2014·PLoS Pathogens
DOI 10.1371/journal.ppat.1004032PMC PMC3961374
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Abstract

The mechanisms of chronic HBV infection and immunopathogenesis are poorly understood due to a lack of a robust small animal model. Here we report the development of a humanized mouse model with both human immune system and human liver cells by reconstituting the immunodeficient A2/NSG (NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice with human HLA-A2 transgene) with human hematopoietic stem cells and liver progenitor cells (A2/NSG-hu HSC/Hep mice). The A2/NSG-hu HSC/Hep mouse supported HBV infection and approximately 75% of HBV infected mice established persistent infection for at least 4 months. We detected human immune responses, albeit impaired in the liver, chronic liver inflammation and liver fibrosis in infected animals. An HBV neutralizing antibody efficiently inhibited HBV infection and associated liver diseases in humanized mice. In addition, we found that the HBV mediated liver disease was associated with high level of infiltrated human macrophages with M2-like activation phenotype. Importantly, similar M2-like macrophage accumulation was confirmed in chronic hepatitis B patients with liver diseases. Furthermore, gene expression analysis showed that induction of M2-like macrophage in the liver is associated with accelerated liver fibrosis and necrosis in patients with acute HBV-induced liver failure. Lastly, we demonstrate that HBV promotes M2-like activation in both M1 and M2 macrophages in cell culture studies. Our study demonstrates that the A2/NSG-hu HSC/Hep mouse model is valuable in studying HBV infection, human immune responses and associated liver diseases. Furthermore, results from this study suggest a critical role for macrophage polarization in hepatitis B virus-induced immune impairment and liver pathology.

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  • In chronic viral hepatitis or parasitic infections, excessive anti-inflammatory polarization may impair pathogen clearance and perpetuate chronic inflammation.

    “In these settings, excessive anti-inflammatory polarization may impair pathogen clearance and perpetuate chronic inflammation, thereby reshaping macrophage function (129–135).”

    From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [132]

    The Discussion states that during chronic HBV infection, M2-like macrophages impair the Th1 response and promote pathogen persistence and associated tissue pathology. This supports the claim for chronic viral hepatitis, but the cited passages do not address parasitic infections. (LLM, conf=0.86)

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Cited by

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Authors
Bility, M. T., Cheng, L., Zhang, Z., Luan, Y., Li, F., Chi, L., Zhang, L., Tu, Z., Gao, Y., Fu, Y., Niu, J., Wang, F., & Su, L.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • 302 Military Hospital of China (CN)
  • Chinese Academy of Sciences (CN)
  • Jilin University (CN)
Corresponding author
  • Bility, Moses T.
  • Su, Lishan
ORCID
Venue
PLoS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2014-03-20
Volume
10
Issue
3
Pages
e1004032
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1004032
PMC
PMC3961374
OpenAlex
W1998976744
Cited by
227
References
1
Citations by year
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FWCI
18.94
Type
journal article
Language
en
Update notices
correction (2015-03-17)
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • Knowledge@UChicago (University of Chicago) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • UNC Libraries
  • University of Chicago (cc-by)
Funders
  • Blood Systems Research Institute
  • National Institutes of Health
  • National Institute on Alcohol Abuse and Alcoholism (R21AA018009, AA018009)
  • National Cancer Institute (R01CA164029)
  • National Institute of Allergy and Infectious Diseases (R01AI095097, R21AI076142, AI076142)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK095962, R01DK100664)
  • Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Topics
  • Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Hepatitis C virus research
Keywords
hepatitis B virus, chronic hepatitis B, immunopathogenesis, humanized mice, human hematopoietic stem cells, liver progenitor cells, liver fibrosis, M2 macrophages, macrophage polarization, liver necrosis, liver failure
MeSH terms
Animals, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Hematopoietic Stem Cells, Hepatitis B virus, Humans, Immunohistochemistry, Liver Cirrhosis, Macrophages, Stem Cells, Transplantation, Heterologous, Mice, Inbred NOD, Hepatitis B, Chronic, Hepatocytes, Mice

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