Transcriptome profiles of Huh7.5.1-NTCP cells treated with HBV preS1 peptide
Ontology highlight
ABSTRACT: Chronic hepatitis B, C and D virus (HBV, HCV, HDV) infections are leading causes of liver disease and cancer worldwide. Although these viruses differ markedly in their life cycle and genomic organization, they exclusively infect hepatocytes. Recently, the sodium taurocholate cotransporting polypeptide (NTCP) was identified as the first functional receptor for HBV and HDV. Here, we report that NTCP also facilitates HCV entry into human hepatocytes, by augmenting the bile acid-mediated repression of IFN-stimulated genes (ISGs), including IFITM2 and IFITM3, to increase the susceptibility of cells to HCV entry. Furthermore, an HBV-derived preS1 peptide, known to bind NTCP and to inhibit bile acid uptake and HBV infection, inhibits HCV entry by enhancing the expression of ISGs. Our study highlights NTCP as a novel player linking bile acid metabolism to the interferon response in hepatocytes and establishes a role for NTCP in the entry process of multiple hepatotropic viruses, via distinct mechanisms. Collectively, these findings enhance our understanding of hepatitis virus-host interactions and suggest NTCP as an attractive antiviral target for HBV/HCV co-infection. Transcriptome profiling by DNA microarray of Huh7.5.1 cells transduced to express NTCP.
Project description:Chronic hepatitis B, C and D virus (HBV, HCV, HDV) infections are leading causes of liver disease and cancer worldwide. Although these viruses differ markedly in their life cycle and genomic organization, they exclusively infect hepatocytes. Recently, the sodium taurocholate cotransporting polypeptide (NTCP) was identified as the first functional receptor for HBV and HDV. Here, we report that NTCP also facilitates HCV entry into human hepatocytes, by augmenting the bile acids-mediated repression of IFN-stimulated genes (ISGs), including IFITM2 and IFITM3, to increase the susceptibility of cells to HCV entry. Furthermore, an HBV-derived preS1 peptide, known to bind NTCP and to inhibit bile acids uptake and HBV infection, inhibits HCV entry by enhancing the expression of ISGs. Our study highlights NTCP as a novel player linking bile acids metabolism to the interferon response in hepatocytes and establishes a role for NTCP in the entry process of multiple hepatotropic viruses, via distinct mechanisms. Collectively, these findings enhance our understanding of hepatitis virus-host interactions and suggest NTCP as an attractive antiviral target for HBV/HCV co-infection.
Project description:Chronic hepatitis B, C and D virus (HBV, HCV, HDV) infections are leading causes of liver disease and cancer worldwide. Although these viruses differ markedly in their life cycle and genomic organization, they exclusively infect hepatocytes. Recently, the sodium taurocholate cotransporting polypeptide (NTCP) was identified as the first functional receptor for HBV and HDV. Here, we report that NTCP also facilitates HCV entry into human hepatocytes, by augmenting the bile acid-mediated repression of IFN-stimulated genes (ISGs), including IFITM2 and IFITM3, to increase the susceptibility of cells to HCV entry. Furthermore, an HBV-derived preS1 peptide, known to bind NTCP and to inhibit bile acid uptake and HBV infection, inhibits HCV entry by enhancing the expression of ISGs. Our study highlights NTCP as a novel player linking bile acid metabolism to the interferon response in hepatocytes and establishes a role for NTCP in the entry process of multiple hepatotropic viruses, via distinct mechanisms. Collectively, these findings enhance our understanding of hepatitis virus-host interactions and suggest NTCP as an attractive antiviral target for HBV/HCV co-infection.
Project description:This project enriched and identified phosphoproteins in human hepatocarcinoma 7.5.1 cell line (Huh7.5.1) upon Hepatitis C virus (HCV) infection.
Project description:Transcription profiling by array of human hepatitis B virus (HBV) and hepatitis C virus (HCV) induced hepatocellular (HCC) carcinoma and surrounding noncancerous liver tissue.
Project description:We applied small RNA Solexa sequencing technology to identify microRNA expression in human liver samples from surgically removed liver tissues including three normal liver tissues (distal normal liver tissue of liver hemangioma), an hepatitis B virus (HBV)-infected liver, a severe chronic hepatitis B liver, two HBV-related hepatocellular carcinoma (HCC), an hepatitis C virus (HCV)-related HCC, and an HCC without HBV or HCV infection. All samples were collected with the informed consent of the patients and the experiments were approved by the ethics committee of Second Military Medical University, Shanghai, China. We investigated the miRNome in human normal liver and suggested some deregulated abundantly expressed microRNAs in HCC. center_name: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China. Examination of miRNome in human liver samples from surgically removed liver tissues including three normal liver tissues (distal normal liver tissue of liver hemangioma), an hepatitis B virus (HBV)-infected liver tissue, a severe chronic hepatitis B liver tissue, an HBV-related hepatocellular carcinoma (HCC) tissue and adjacent liver tissues of different regions,an HBV-related HCC tissue and adjacent liver tissue, an hepatitis C virus (HCV)-related HCC tissue and adjacent liver tissue, and an HCC without HBV or HCV infection and adjacent liver tissue. All 15 human liver tissue samples.
Project description:The liver, and more precisely hepatocytes, can be infected by several viruses such as hepatitis B (HBV), hepatitis D (HDV), hepatitis C (HCV), hepatitis E (HEV) viruses, with chronic infection leading to end-stage liver diseases. Since no in vitro model allowing multi-infections with the four viruses is reported, limited data are available on the interplay between those viruses as well as on the potential cross-reactivity of antivirals in multi-infection cases. Here we showed that HuH7.5-NTCP cells can be partially differentiated into hepatocyte-like cells and genuinely replicate HBV, HDV, HCV and HEV for at least 4 weeks after mono or multiple infections. Additionally, we recapitulated the effect of known antivirals and found that FXR-agonists, also strongly inhibited HEV replication. Using HEV infected HuHep mice, we confirmed the antiviral effect of Vonafexor, the FXR agonist clinical candidate currently tested against HBV and HDV, highlighting FXR-ligands as potential broad acting antivirals. Here, we set-up the first in vitro model allowing multi-infections with hepatitis viruses that can be used for broad drug screening.
Project description:Virus species- and tissue-tropism is governed by host dependency and restriction factors. Hepatitis C virus (HCV) exhibits a narrow species-tropism and murine hepatocytes are refractory to infection. Using murine liver cDNA library screening we identified Cd302, a lectin, and Cr1l, a complement receptor, as pan-genotypic restrictors of HCV infection. Cd302/Cr1l interact to impede virion uptake and co-operatively induce a non-canonical transcriptional program, inhibiting HCV and hepatitis B virus (HBV) infection in vitro. CAS9 disruption of murine hepatocyte Cd302 expression increased HCV permissiveness in-vivo and ex-vivo, and modulated the intrinsic hepatocyte transcriptome dysregulating metabolic process and host defense genes. In contrast, co-operative CD302/CR1L expression was absent and HCV restriction reduced in human hepatocytes. The Cd302/Cr1l axis therefore contributes to limiting hepatotropic virus cross-species transmission to mice, opening new avenues for step-wise development of mouse models for these important human pathogens, which cause substantial disease burden globally.
Project description:Virus species- and tissue-tropism is governed by host dependency and restriction factors. Hepatitis C virus (HCV) exhibits a narrow species-tropism and murine hepatocytes are refractory to infection. Using murine liver cDNA library screening we identified Cd302, a lectin, and Cr1l, a complement receptor, as pan-genotypic restrictors of HCV infection. Cd302/Cr1l interact to impede virion uptake and co-operatively induce a non-canonical transcriptional program, inhibiting HCV and hepatitis B virus (HBV) infection in vitro. CAS9 disruption of murine hepatocyte Cd302 expression increased HCV permissiveness in-vivo and ex-vivo, and modulated the intrinsic hepatocyte transcriptome dysregulating metabolic process and host defense genes. In contrast, co-operative CD302/CR1L expression was absent and HCV restriction reduced in human hepatocytes. The Cd302/Cr1l axis therefore contributes to limiting hepatotropic virus cross-species transmission to mice, opening new avenues for step-wise development of mouse models for these important human pathogens, which cause substantial disease burden globally.
Project description:Virus species- and tissue-tropism is governed by host dependency and restriction factors. Hepatitis C virus (HCV) exhibits a narrow species-tropism and murine hepatocytes are refractory to infection. Using murine liver cDNA library screening we identified Cd302, a lectin, and Cr1l, a complement receptor, as pan-genotypic restrictors of HCV infection. Cd302/Cr1l interact to impede virion uptake and co-operatively induce a non-canonical transcriptional program, inhibiting HCV and hepatitis B virus (HBV) infection in vitro. CAS9 disruption of murine hepatocyte Cd302 expression increased HCV permissiveness in-vivo and ex-vivo, and modulated the intrinsic hepatocyte transcriptome dysregulating metabolic process and host defense genes. In contrast, co-operative CD302/CR1L expression was absent and HCV restriction reduced in human hepatocytes. The Cd302/Cr1l axis therefore contributes to limiting hepatotropic virus cross-species transmission to mice, opening new avenues for step-wise development of mouse models for these important human pathogens, which cause substantial disease burden globally.
Project description:Virus species- and tissue-tropism is governed by host dependency and restriction factors. Hepatitis C virus (HCV) exhibits a narrow species-tropism and murine hepatocytes are refractory to infection. Using murine liver cDNA library screening we identified Cd302, a lectin, and Cr1l, a complement receptor, as pan-genotypic restrictors of HCV infection. Cd302/Cr1l interact to impede virion uptake and co-operatively induce a non-canonical transcriptional program, inhibiting HCV and hepatitis B virus (HBV) infection in vitro. CAS9 disruption of murine hepatocyte Cd302 expression increased HCV permissiveness in-vivo and ex-vivo, and modulated the intrinsic hepatocyte transcriptome dysregulating metabolic process and host defense genes. In contrast, co-operative CD302/CR1L expression was absent and HCV restriction reduced in human hepatocytes. The Cd302/Cr1l axis therefore contributes to limiting hepatotropic virus cross-species transmission to mice, opening new avenues for step-wise development of mouse models for these important human pathogens, which cause substantial disease burden globally.