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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]

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

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  • Media type: E-Article
  • Title: Hepatitis D infection induces IFN-β-mediated NK cell activation and TRAIL-dependent cytotoxicity
  • Contributor: Groth, Christopher [VerfasserIn]; Maric, Jovana [VerfasserIn]; Garcés Lázaro, Irene [VerfasserIn]; Hofman, Tomáš [VerfasserIn]; Zhang, Zhenfeng [VerfasserIn]; Ni, Yi [VerfasserIn]; Keller, Franziska [VerfasserIn]; Seufert, Isabelle [VerfasserIn]; Hofmann, Maike [VerfasserIn]; Neumann-Haefelin, Christoph [VerfasserIn]; Sticht, Carsten [VerfasserIn]; Rippe, Karsten [VerfasserIn]; Urban, Stephan [VerfasserIn]; Cerwenka, Adelheid [VerfasserIn]
  • imprint: 08 December 2023
  • Published in: Frontiers in immunology ; 14(2023) vom: Dez., Artikel-ID 1287367, Seite 1-15
  • Language: English
  • DOI: 10.3389/fimmu.2023.1287367
  • ISSN: 1664-3224
  • Identifier:
  • Keywords: HBV ; HDV ; IFN-beta ; NK cells ; TRAIL
  • Origination:
  • Footnote:
  • Description: <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>
  • Access State: Open Access