Des souris humanisées pour l’étude du virus de l’hépatite C

Gilgenkrantz, Hélène

doi:10.1051/medsci/2011276009

Cited by 7 publications

(4 citation statements)

References 11 publications

(7 reference statements)

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“…However, HBV is endemic in many developing countries with over 350 million people worldwide chronically infected [10]. Delineation of the mechanisms by which HBV evades host immunity to establish chronic infection and promote liver disease is hampered by the lack of robust animal models [11], [12], [13].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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-Prkdcscid Il2rgtm1Wjl/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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Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…The development of direct-acting antiviral (DAA) drugs has played a significant role in controlling chronic HCV infection and associated liver disease; however liver fibrosis and HCC development and progression is still a major problem in chronically infected patients1. Delineation of the mechanisms by which HCV evades host immunity to establish chronic infection and promote liver disease is a major hurdle in treating chronic HCV-induced advanced liver disease234. HCV and other human hepatotropic pathogens including HBV have host species restriction, namely humans and chimpanzees3.…”

mentioning

confidence: 99%

Chronic hepatitis C infection–induced liver fibrogenesis is associated with M2 macrophage activation

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Nio

et al. 2016

Sci Rep

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The immuno-pathogenic mechanisms of chronic hepatitis C virus (HCV) infection remain to be elucidated and pose a major hurdle in treating or preventing chronic HCV-induced advanced liver diseases such as cirrhosis. Macrophages are a major component of the inflammatory milieu in chronic HCV–induced liver disease, and are generally derived from circulating inflammatory monocytes; however very little is known about their role in liver diseases. To investigate the activation and role of macrophages in chronic HCV–induced liver fibrosis, we utilized a recently developed humanized mouse model with autologous human immune and liver cells, human liver and blood samples and cell culture models of monocyte/macrophage and/or hepatic stellate cell activation. We showed that M2 macrophage activation was associated with liver fibrosis during chronic HCV infection in the livers of both humanized mice and patients, and direct-acting antiviral therapy attenuated M2 macrophage activation and associated liver fibrosis. We demonstrated that supernatant from HCV-infected liver cells activated human monocytes/macrophages with M2-like phenotypes. Importantly, HCV-activated monocytes/macrophages promoted hepatic stellate cell activation. These results suggest a critical role for M2 macrophage induction in chronic HCV-associated immune dysregulation and liver fibrosis.

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“…However, there remains a lack of robust animal models to investigate the underlying mechanism by which HBV escapes host immunity to cause chronic infection and liver disorders. 7 MicroRNAs (miRNAs) play a role in the improvement of numerous species and are commonly associated with genetic disorders, including cancer. 8 MicroRNAs exert their effects by targeting mRNA and downregulating gene expression.…”

Section: Introductionmentioning

confidence: 99%

Role of microRNA 4717, its effects on programmed cell death protein-1 in hepatitis B infection, and interaction between PDCD1 and miR-4717

Li¹,

2020

Eur J Inflamm

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It is suggested that programmed cell death protein-1 (PD-1) is involved in hepatitis B virus (HBV) infection, the leading cause of hepatocellular carcinoma globally. This study was multi-aimed, that is, to investigate the role of microRNA (miR) 4717 and its target, PD-1 and to determine how the rs10204525 polymorphism in the 3′ untranslated region (3′UTR) of PD-1 affects its interaction with miR-4717. The expression levels of miR-4717 with various single-nucleotide polymorphisms were measured by reverse transcription–quantitative polymerase chain reaction (RT-qPCR). A total of 54 tissue samples from HBV-infected individuals were collected, genotyped, and categorized into three groups; AA (n = 32), AG (n = 18), and GG (n = 4). The expression levels of gene PDCD1 and its corresponding PD-1 protein were significantly declined in the AA group as compared to AG and GG groups. There was a negative linear association between PDCD1 and miR-4717 in the tissue samples. HEPG2 cells transfected with an miR-4717 mimic or PD-1 small interfering (si)RNA exhibited significantly reduced expression levels of PDCD1 and PD-1, whereas cells transfected with an inhibitor of miR-4717 demonstrated greater expression levels of PDCD1 and PD-1 compared with the scramble control. In addition, cell viability and apoptosis were assessed in cells transfected with an miR-4717 mimic, PD-1 siRNA, or an miR-4717 inhibitor. Results revealed that treatment with the miR-4717 mimic or PD-1 siRNA enhanced viability of cells and reduced apoptosis. The results of this study suggest that rs10204525 polymorphism interferes with the interaction between PD-1 and miR-4717 and therefore induces apoptosis in liver cancer cells.

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Des souris humanisées pour l’étude du virus de l’hépatite C

Cited by 7 publications

References 11 publications

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

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

Chronic hepatitis C infection–induced liver fibrogenesis is associated with M2 macrophage activation

Role of microRNA 4717, its effects on programmed cell death protein-1 in hepatitis B infection, and interaction between PDCD1 and miR-4717

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