New horizons for studying human hepatotropic infections

Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10065, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 02/2010; 120(3):650-3. DOI: 10.1172/JCI42338
Source: PubMed


The liver serves as a target organ for several important pathogens, including hepatitis B and C viruses (HBV and HCV, respectively) and the human malaria parasites, all of which represent serious global health problems. Because these pathogens are restricted to human hepatocytes, research in small animals has been compromised by the frailty of the current mouse xenotransplantation models. In this issue of the JCI, Bissig et al. demonstrate robust HBV and HCV infection in a novel xenotransplantation model in which large numbers of immunodeficient mice with liver injury were engrafted with significant quantities of human hepatocytes. This technical advance paves the way for more widespread use of human liver chimeric mice and forms the basis for creating increasingly complex humanized mouse models that could prove useful for studying immunopathogenesis and vaccine development against hepatotropic pathogens.

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    • "Since HCV does not readily replicate in non-human species conceptually the most straightforward strategy would be to introduce the relevant tissue compartment – a human liver – into mice. To this end various approaches have been taken including transplantation of human liver pieces under the kidney capsule (Ilan et al., 2002), engraftment of ''human ectopic artificial livers'' (HEALs) in the peritoneal cavity (Chen et al., 2011) or actual expansion of human hepatocytes within the liver parenchyma (reviewed in de Jong et al. (2010) and Meuleman and Leroux- Roels (2008b) of immunocompromised mice. For the latter approach, suitable xenorecipients combine two features; immunodeficiency to prevent graft rejection and liver injury to provide a growth stimulus for the normally quiescent hepatocytes as well as yield the transplanted human cells a competitive growth advantage over endogenous murine cells. "
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    ABSTRACT: Hepatitis C virus (HCV) is a major causative agent of severe liver disease including fibrosis, cirrhosis and liver cancer. Therapy has improved over the years, but continues to be associated with adverse side effects and variable success rates. Furthermore, a vaccine protecting against HCV infection remains elusive. Development of more effective intervention measures has been delayed by the lack of a suitable animal model. Naturally, HCV infects only humans and chimpanzees. The determinants of this limited host range are poorly understood in part due to difficulties of studying HCV in cell culture. Some progress has been made elucidating the barriers for the HCV lifecycle in non-permissive species which will help in the future to construct animal models for HCV infection, immunity and pathogenesis.
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    • "To address this problem, we (Hasegawa et al., 2011) and others (reviewed in Yoshizato and Tateno, 2009; de Jong et al., 2010) have developed chimeric mice, in which mouse liver is replaced by transplanted human liver cells or tissue-engineered human liver (Chen et al., 2011). In one model system, uroplasminogen activator transgene expression facilitates the growth of transplanted human liver cells (Vyse et al., 1997; Tateno et al., 2004; Meuleman et al., 2005; Azuma et al., 2007; Katoh and Yokoi, 2007), whereas a fumarylacetoacetate hydrolase knockout mouse is used in the other system (Azuma et al., 2007) (Bissig et al., 2010). "
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    Full-text · Article · Nov 2012 · Journal of Pharmacology and Experimental Therapeutics
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    • "In addition to replicons, defined infectious strains (Cai et al., 2005; Wakita et al., 2005) and patient wild type viruses (Castet et al., 2002; Gondeau et al., 2009) have been passed in primary hepatocytes and other permissive cell lines. Recently, reliable chimeric mouse-human models for in vivo testing of antiviral activity have also been introduced (Bissig et al., 2007, 2010; de Jong et al., 2010; Washburn et al., 2011). "
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    ABSTRACT: Hepatitis C virus, human immunodeficiency virus, and hepatitis B virus are chronic viral infections that cause considerable morbidity and mortality throughout the world. In the decades following the identification and sequencing of these viruses, in vitro experiments demonstrated that heme oxygenase-1, its oxidative products, and related compounds of the heme oxygenase system inhibit replication of all 3 viruses. The purpose of this review is to critically evaluate and summarize the seminal studies that described and characterized this remarkable behavior. It will also discuss more recent work that discovered the antiviral mechanisms and target sites of these unique antiviral agents. In spite of the fact that these viruses are diverse pathogens with quite profound differences in structure and life cycle, it is significant that heme and related compounds show striking similarity for viral target sites across all three species. Collectively, these findings strongly indicate that we should move forward and develop heme and related tetrapyrroles into versatile antiviral agents that could be used therapeutically in patients with single or multiple viral infections.
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