Characterisation of liver pathogenesis, human immune responses and drug testing in a humanised mouse model of HCV infection

Abstract

ObjectiveHCV infection affects millions of people worldwide, and many patients develop chronic infection leading to liver cancers. For decades, the lack of a small animal model that can recapitulate HCV infection, its immunopathogenesis and disease progression has impeded the development of an effective vaccine and therapeutics. We aim to provide a humanised mouse model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies.DesignRecently, we have established human liver cells with a matched human immune system in NOD-scid Il2rg−/− (NSG) mice (HIL mice). These mice are infected with HCV by intravenous injection, and the pathologies are investigated.ResultsIn this study, we demonstrate that HIL mouse is capable of supporting HCV infection and can present some of the clinical symptoms found in HCV-infected patients including hepatitis, robust virus-specific human immune cell and cytokine responses as well as liver fibrosis and cirrhosis. Similar to results obtained from the analysis of patient samples, the human immune cells, particularly T cells and macrophages, play critical roles during the HCV-associated liver disease development in the HIL mice. Furthermore, our model is demonstrated to be able to reproduce the therapeutic effects of human interferon alpha 2a antiviral treatment.ConclusionsThe HIL mouse provides a model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. It could also serve as a platform for antifibrosis and immune-modulatory drug testing.

Hepatitis C virus mediated chronic inflammation and tumorigenesis in the Humanised Immune system and Liver mouse model

“…As shown in our previous work, the increased numbers of activated CD4 + T cells accounted for the elevated levels of plasma IFN-γ in infected HIL mice [25].…”

Humanized Mice as Unique Tools for Human-Specific Studies

“…These inventions cascaded into a series of immunodeficient mice and their variants (BRG, NOG, NRG) (Ali et al 2012; Grover et al 2017; Ishikawa et al 2005; Katano et al 2014; Koboziev et al 2015; Shultz et al 2005) being innovated which enabled in-depth analysis in research areas, such as human hematopoiesis (Rongvaux et al 2011; Yong et al 2016), innate and adaptive immunity (Brehm et al 2010; Pearson et al 2008), autoimmunity (Gunawan et al 2017; Viehmann Milam et al 2014), infectious disease (Keng et al 2015; Lüdtke et al 2015; Wege et al 2012), cancer biology (Chang et al 2015; Her et al 2017; Morton et al 2016), and GvHD (King et al 2008; Kirkiles-Smith et al 2009; Zhao et al 2015), in-turn, facilitating the development of therapeutic agents and novel vaccines. An overview of genotypic and physiological characteristics of each model is outlined in Tables 1 and 2.…”

“…injection of human peripheral blood mononuclear cells (PBMCs) into mice (Hu-PBL- scid ) (Duchosal et al 1992; Harui et al 2011; King et al 2008; Tary-Lehmann et al 1995), injecting CD34 + HSCs obtained from human fetal liver (FL), umbilical cord blood (UBC), bone marrow (BM) or granulocyte-colony-stimulating factor (G-CSF) mobilised peripheral blood (Hu-SRC- scid ) (Brehm et al 2010; Chen et al 2009, 2012, 2015; Keng et al 2015; Yong et al 2016), or i.v. injection of FL HSCs and BM cells paired with transplantation of matching FL and thymus under the kidney capsule to obtain a BM/liver/thymus (BLT) mouse model (Brainard et al 2009; Covassin et al 2013; Denton et al 2008; Lan et al 2004, 2006; Melkus et al 2006; Tonomura et al 2008).…”

“…In addition to the human immune system, recent progress has been made to introduce humanization of the liver in humanized mice to support the study of hepatotropic pathogens such as hepatitis B virus and hepatitis C virus (HCV) (Bility et al 2012; Keng et al 2015; Strick-Marchand et al 2015; Tan-Garcia et al 2017; Washburn et al 2011). It has been shown that these new humanized mice could be infected with human strains of hepatitis viruses and exhibit leukocyte infiltrations, liver inflammation, fibrosis, cirrhosis, and elevated cytokines similar to HCV-infected patients (Bility et al 2014; Keng et al 2015; Tan-Garcia et al 2017; Washburn et al 2011).…”

Metalloproteinases in liver fibrosis: current insights

“…Finally, humanized mice with human immune system and hepatocytes is the only model, which upon infection triggers responses similar to humans, i.e., hepatitis and fibrosis. [44][45][46][47] Genetically modified mice Genetically modified animals are becoming a more frequent tool to study liver pathophysiology as well as the roles of metalloproteinases. The liver consists of several cell types and it is not easy to target them specifically.…”