Targeted Induction of Interferon-λ in Humanized Chimeric Mouse Liver Abrogates Hepatotropic Virus Infection

Abstract

Background & AimsThe interferon (IFN) system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV) and hepatitis B virus (HBV).MethodsThis study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC). Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs) in the livers and sera of these humanized chimeric mice.ResultsFollowing treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level) of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic) tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1), suggesting dual recognition of LIC-pIC by both sensor adaptor pathways.ConclusionsThese findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.

Contribution of type III interferons to antiviral immunity: location, location, location

“…However, experiments carried out in vivo are revealing a much more nuanced and complex picture. Mucosal infections appear to trigger predominantly IFNexpression and a low level of IFN-␤ (32,33). The source of these IFNs is often epithelial cells, which preferentially express IFN-s (34 -41).…”

Interferon-λ in the Context of Viral Infections: Production, Response and Therapeutic Implications

“…The above data suggest that IFN-λ responses strongly differ between human and mouse hepatocytes. In a model of chimeric mice engrafted with human hepatocytes, the gene encoding IFNLR1 was more strongly expressed in human than in mouse hepatocytes [29] . Our own data support these observations and show that human but not mouse hepatocytes respond to IFN-λ in chimeric mice treated with IFN-λ.…”

“…IFN-λ mRNA expression was induced in response to experimental HCV infection of human fetal liver cells or in patients with chronic HCV infection [42,47] . More recently, in a model of chimeric mice transplanted with human hepatocytes, it was reported that IFN-λ was expressed and produced by human hepatocytes at a greater level than IFN-α or IFN-β in response to poly(I:C) treatment [29] . Interestingly, in the same study, human IFN-λ expression was more strongly induced in HepG2 cells than in HEK293T and MRC-5 cells (kidney and fibroblast cell lines, respectively), whereas the opposite pattern was observed for the expression of IFN-β.…”

Immune-modulators to combat hepatitis B virus infection: From IFN-α to novel investigational immunotherapeutic strategies

“…It is likely that type-III IFNs will also impact on the stability of cccDNA by an APOBEC3A-mediated MOA , but this remains to be firmly demonstrated using ad hoc models and kinetics of treatment allowing cccDNA degradation. If no direct injection of IFN-s was attempted in HBV-infected liver-humanized mice, it was shown that targeted induction of these IFN-s, by injection of hepatotropic cationic-liposome containing a synthetic double-stranded RNA analog poly(I:C) in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 12 the liver microenvironment, could lead to a strong HBV inhibitory phenotype in this animal model (Nakagawa et al, 2013).…”