Inhibition of interferon-α-induced signaling by hyperosmolarity and hydrophobic bile acids

Graf, Dirk; Haselow, Katrin; Münks, Ivo; Bode, Johannes G.; Häussinger, Dieter

doi:10.1515/bc.2010.108

Cited by 17 publications

(21 citation statements)

References 51 publications

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“…Given that the physiological function of NTCP is to transport bile acids, and bile acids are known to affect ISG expression in hepatocytes (Graf et al., 2010, Podevin et al., 1999), we hypothesized that bile acid transport by NTCP regulates the expression of ISGs and viral infection. Since IFITM3 functions as an HCV restriction factor in our model system (Figure 4D), we selected IFITM3 as a representative ISG for functional studies to probe the link between NTCP and the IFN response.…”

Section: Resultsmentioning

confidence: 99%

Solute Carrier NTCP Regulates Innate Antiviral Immune Responses Targeting Hepatitis C Virus Infection of Hepatocytes

et al. 2016

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SummaryChronic hepatitis B, C, and D virus (HBV, HCV, and HDV) infections are the leading causes of liver disease and cancer worldwide. Recently, the solute carrier and sodium taurocholate co-transporter NTCP has been identified as a receptor for HBV and HDV. Here, we uncover NTCP as a host factor regulating HCV infection. Using gain- and loss-of-function studies, we show that NTCP mediates HCV infection of hepatocytes and is relevant for cell-to-cell transmission. NTCP regulates HCV infection by augmenting the bile-acid-mediated repression of interferon-stimulated genes (ISGs), including IFITM3. In conclusion, our results uncover NTCP as a mediator of innate antiviral immune responses in the liver, and they establish a role for NTCP in the infection process of multiple viruses via distinct mechanisms. Collectively, our findings suggest a role for solute carriers in the regulation of innate antiviral responses, and they have potential implications for virus-host interactions and antiviral therapies.

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Section: Resultsmentioning

confidence: 99%

Solute Carrier NTCP Regulates Innate Antiviral Immune Responses Targeting Hepatitis C Virus Infection of Hepatocytes

et al. 2016

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“…However, no specific association was found between the expression of MxA or PKR mRNAs and the different antiviral activities of the type I IFNs against hMPV. Although the protein levels of MxA and PKR were not measured, and taking into consideration that in several studies researchers found a correlation between mRNA-levels and protein changes (8,11,13,15), these data suggest that these two proteins are not responsible for the differing antiviral activities displayed in these cells by the different type I IFNs.…”

Section: Resultsmentioning

confidence: 76%

In VitroSensitivity of Human Metapneumovirus to Type I Interferons

et al. 2011

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Human metapneumovirus (hMPV) has been recognized as an important respiratory pathogen. Due to its relatively recent discovery, only limited information is available on the relationship between hMPV and type I interferons (IFN). This study was designed to determine whether in vitro hMPV is sensitive to the antiviral activity of IFN-β, leukocyte IFN-α, and several IFN-α subtypes in a human Hep-2 cell line. The results showed that 50% inhibitory concentration values against hMPV for the various type I IFN preparations were significantly higher than those against the IFN-sensitive vesicular stomatitis virus, and some IFN-α subtypes appeared to be more active against hMPV than others, with IFN-α subtypes 5, 6, 8, and 10 being the most potent, and IFN-α2, 17, and 21 the least potent. The results show that hMPV grown in Hep-2 is partially resistant to the antiviral activity of type I IFNs. Additional studies are required to understand whether and to what extent the relatively low sensitivity of hMPV to IFNs influences the clinical outcomes of infected individuals.

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“…Recently, bile acids have been shown to impair IFN signaling (31). Therefore, the impact of IFN signaling on the antiviral effect of TCDC on MCMV was tested.…”

Section: Fig 1 Conjugated Bile Acids Act Antivirally Against Mouse Cymentioning

confidence: 99%

“…Gastrointestinal and hepatotrophic viruses replicate in the presence of bile acids that influence cellular signaling, innate and adaptive immune responses (22,29,30), and interferon (IFN) signaling (31). Hepatitis C virus (HCV) and hepatitis B virus (HBV) benefit from bile acid-dependent FXR activation (32,33), while for rotaviruses a significantly reduced fecal shedding was shown at 1 and 3 days postinfection in chenodeoxycholic acid-fed mice (34).…”

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confidence: 99%

Bile Acids Act as Soluble Host Restriction Factors Limiting Cytomegalovirus Replication in Hepatocytes

Schupp

Trilling

Rattay

et al. 2016

J Virol

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The liver constitutes a prime site of cytomegalovirus (CMV) replication and latency. Hepatocytes produce, secrete, and recycle a chemically diverse set of bile acids, with the result that interactions between bile acids and cytomegalovirus inevitably occur. Here we determined the impact of naturally occurring bile acids on mouse CMV (MCMV) replication. In primary mouse hepatocytes, physiological concentrations of taurochenodeoxycholic acid (TCDC), glycochenodeoxycholic acid, and to a lesser extent taurocholic acid significantly reduced MCMV-induced gene expression and diminished the generation of virus progeny, while several other bile acids did not exert antiviral effects. The anticytomegalovirus activity required active import of bile acids via the sodium-taurocholate-cotransporting polypeptide (NTCP) and was consistently observed in hepatocytes but not in fibroblasts. Under conditions in which alpha interferon (IFN-␣) lacks antiviral activity, physiological TCDC concentrations were similarly effective as IFN-␥. A detailed investigation of distinct steps of the viral life cycle revealed that TCDC deregulates viral transcription and diminishes global translation in infected cells. IMPORTANCECytomegaloviruses are members of the Betaherpesvirinae subfamily. Primary infection leads to latency, from which cytomegaloviruses can reactivate under immunocompromised conditions and cause severe disease manifestations, including hepatitis. The present study describes an unanticipated antiviral activity of conjugated bile acids on MCMV replication in hepatocytes. Bile acids negatively influence viral transcription and exhibit a global effect on translation. Our data identify bile acids as site-specific soluble host restriction factors against MCMV, which may allow rational design of anticytomegalovirus drugs using bile acids as lead compounds. C ytomegaloviruses (CMV) are members of the Betaherpesvirinae subfamily and persist for life in infected individuals during alternating phases of latency and productive reactivation. Seroprevalence studies indicate that the large majority of the global human population is currently infected with human cytomegalovirus (HCMV) (human herpesvirus 5 [HHV-5]; taxonomy ID 10359). Although HCMV-related fatalities in apparently healthy individuals sporadically occur (1, 2), HCMV replication usually remains subclinical. This drastically changes under immunocompromising conditions, where untreated CMV infections often cause overt disease, including hepatitis (3) and dysfunction, bleeding, ulceration, and perforation of organs of the upper as well as lower gastrointestinal tract (4). HCMV hepatitis is particularly common in liver transplant recipients and is associated with organ dysfunction and graft failure (5-9).The species specificity of CMV precludes meaningful in vivo experimentation with HCMV in small animal models. Therefore, the homologous mouse CMV (MCMV) (Murid herpesvirus 1, taxonomy ID 10366), which infects Mus musculus (taxonomy ID 10090) as its natural host, has been estab...

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Inhibition of interferon-α-induced signaling by hyperosmolarity and hydrophobic bile acids

Cited by 17 publications

References 51 publications

Solute Carrier NTCP Regulates Innate Antiviral Immune Responses Targeting Hepatitis C Virus Infection of Hepatocytes

Solute Carrier NTCP Regulates Innate Antiviral Immune Responses Targeting Hepatitis C Virus Infection of Hepatocytes

In VitroSensitivity of Human Metapneumovirus to Type I Interferons

Bile Acids Act as Soluble Host Restriction Factors Limiting Cytomegalovirus Replication in Hepatocytes

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