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Hepatitis D infection induces IFN-β-mediated NK cell activation and TRAIL-dependent cytotoxicity

<sec><title>Background and aims</title><p>The co-infection of hepatitis B (HBV) patients with the hepatitis D virus (HDV) causes the most severe form of viral hepatitis and thus drastically worsens the course of the disease. Therapy options for HBV/HDV patients are still limi...

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Main Authors: Groth, Christopher (Author) , Maric, Jovana (Author) , Garcés Lázaro, Irene (Author) , Hofman, Tomáš (Author) , Zhang, Zhenfeng (Author) , Ni, Yi (Author) , Keller, Franziska (Author) , Seufert, Isabelle (Author) , Hofmann, Maike (Author) , Neumann-Haefelin, Christoph (Author) , Sticht, Carsten (Author) , Rippe, Karsten (Author) , Urban, Stephan (Author) , Cerwenka, Adelheid (Author)
Format: Article (Journal)
Language:English
Published: 08 December 2023
In: Frontiers in immunology
Year: 2023, Volume: 14, Pages: 1-15
ISSN:1664-3224
DOI:10.3389/fimmu.2023.1287367
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.3389/fimmu.2023.1287367
Verlag, kostenfrei, Volltext: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1287367/full
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Author Notes:Christopher Groth, Jovana Maric, Irene Garcés Lázaro, Tomáš Hofman, Zhenfeng Zhang, Yi Ni, Franziska Keller, Isabelle Seufert, Maike Hofmann, Christoph Neumann-Haefelin, Carsten Sticht, Karsten Rippe, Stephan Urban and Adelheid Cerwenka
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Summary:<sec><title>Background and aims</title><p>The co-infection of hepatitis B (HBV) patients with the hepatitis D virus (HDV) causes the most severe form of viral hepatitis and thus drastically worsens the course of the disease. Therapy options for HBV/HDV patients are still limited. Here, we investigated the potential of natural killer (NK) cells that are crucial drivers of the innate immune response against viruses to target HDV-infected hepatocytes.</p></sec><sec><title>Methods</title><p>We established <italic>in vitro</italic> co-culture models using HDV-infected hepatoma cell lines and human peripheral blood NK cells. We determined NK cell activation by flow cytometry, transcriptome analysis, bead-based cytokine immunoassays, and NK cell-mediated effects on T cells by flow cytometry. We validated the mechanisms using CRISPR/Cas9-mediated gene deletions. Moreover, we assessed the frequencies and phenotype of NK cells in peripheral blood of HBV and HDV superinfected patients.</p></sec><sec><title>Results</title><p>Upon co-culture with HDV-infected hepatic cell lines, NK cells upregulated activation markers, interferon-stimulated genes (ISGs) including the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), produced interferon (IFN)-γ and eliminated HDV-infected cells via the TRAIL-TRAIL-R2 axis. We identified IFN-β released by HDV-infected cells as an important enhancer of NK cell activity. In line with our <italic>in vitro</italic> data, we observed activation of peripheral blood NK cells from HBV/HDV co-infected, but not HBV mono-infected patients.</p></sec><sec><title>Conclusion</title><p>Our data demonstrate NK cell activation in HDV infection and their potential to eliminate HDV-infected hepatoma cells via the TRAIL/TRAIL-R2 axis which implies a high relevance of NK cells for the design of novel anti-viral therapies.</p></sec>
Item Description:Gesehen am 19.03.2024
Physical Description:Online Resource
ISSN:1664-3224
DOI:10.3389/fimmu.2023.1287367

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