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Comprehensive immune profile changes to human interferon stimulation in normal and HBV-infected conditions in a humanized mouse I

ABSTRACT: The underlying mechanism of chronic hepatitis B virus (HBV) functional cure by interferon (IFN), especially in patients with low HBsAg or/and young ages, is still unresolved for lacking surrogate models. Here, we generated a type I interferon receptor humanized mouse (huIFNAR mouse) through a CRISPR/Cas9-based knock-in strategy. Then, we demonstrated that human IFN stimulated a similar gene expression profile of huIFNAR peripheral blood mononuclear cells (PBMC) to what in human PBMCs, supporting the representativeness of the novel mouse model in functionally analyzing human IFN in vivo. Next, we revealed a markedly tissue-specific gene expression atlas against human IFN treatment in the multiple organs less appreciated in healthy humans in vivo. Finally, using the AAV-HBV model, we test the antiviral effects of human interferon in this mouse. Fifteen-week human PEG-IFNα2 treatment significantly reduced HBsAg and HBeAg and even achieved HBsAg seroconversion. We observed that activation of intrahepatic monocytes and effector memory CD8 T cells by human interferon might be critical for HBsAg suppression. In conclusion, our novel huIFNAR mouse can authentically respond to human Interferon stimulation, providing a novel platform to study interferon function in vivo. The PEG-IFNα2 treatment successfully suppresses intrahepatic HBV replication and achieved HBsAg seroconversion in some mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE236814 | GEO | 2023/09/24

REPOSITORIES: GEO

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Project description:The molecular mechanisms whereby hepatitis B virus (HBV) induces hepatocellular carcinoma (HCC) remain elusive. We used genomic and molecular techniques to investigate host-virus interactions by mapping the entire liver of patients with HCC. We compared the gene signature of whole liver tissue (WLT) versus laser capture-microdissected (LCM) hepatocytes with intrahepatic expression of HBV. Gene expression profiling was performed on up to 17 WLT specimens obtained at various distances from the tumor center in individual livers of 11 patients with HCC and on selected LCM samples. HBV biomarkers were determined by real-time PCR and confocal immunofluorescence. Analysis of 5 areas of the liver showed a sharp change in gene expression between the immediate perilesional area and tumor periphery that correlated with a significant decrease in the intrahepatic expression of HBsAg. The tumor was characterized by a large preponderance of down-regulated genes, mostly involved in the metabolism of lipid and fatty acid, glucose, amino acids and drugs, with down-regulation of pathways involved in the activation of PXR/RXR and PPARa/RXRa nuclear receptors, comprising PGC1 and FOXO1, two key regulators of the hepatic metabolic functions and HBV transcription. These findings were confirmed by gene expression of microdissected hepatocytes. However, LCM of malignant hepatocytes also revealed up-regulation of unique genes associated with cancer and signaling pathways, including two novel HCC-associated cancer testis antigen (CTA) genes, NUF2 and TTK. HCC-associated with HBV is characterized by a metabolism switch-off and by a significant reduction in HBsAg. LCM proved to be a critical tool to validate gene signatures associated with HCC and to identify genes that may play a role in hepatocarcinogenesis opening new perspectives for the discovery of novel diagnostic markers and therapeutic targets. Samples were obtained at various distances from the tumor center in individual livers of 11 patients with HBV-associated HCC. Whole liver tissue samples were compared to LCM samples of malignant and non-malignant hepatocytes obtained from the same livers. This dataset is part of the TransQST collection.

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Comprehensive immune profile changes to human interferon stimulation in normal and HBV-infected conditions in a humanized mouse I

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