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

Christopher Groth1, Jovana Maric1, Irene Garcés Lázaro1

  • 1Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Frontiers in Immunology
|December 25, 2023
PubMed

Insights

Natural killer (NK) cells are activated by hepatitis D virus (HDV) infection and can eliminate infected liver cells. This finding highlights NK cells as a potential target for novel antiviral therapies against HBV/HDV co-infection.

Area of Science:

  • Immunology
  • Hepatology
  • Virology

Background:

  • Hepatitis B virus (HBV) and hepatitis D virus (HDV) co-infection leads to severe viral hepatitis with limited treatment options.
  • Natural killer (NK) cells are key players in the innate immune response against viral infections.

Purpose of the Study:

  • To investigate the potential of NK cells to target hepatocytes infected with HDV.
  • To explore the mechanisms of NK cell activation and function in the context of HDV infection.

Main Methods:

  • Co-culture models of HDV-infected hepatoma cell lines and human NK cells.
  • Flow cytometry, transcriptome analysis, and cytokine immunoassays to assess NK cell activation.
  • CRISPR/Cas9 gene editing to validate mechanisms and analysis of NK cells in HBV/HDV patients.

Main Results:

  • NK cells upregulated activation markers and interferon-stimulated genes (ISGs), including TRAIL, upon co-culture with HDV-infected cells.
  • NK cells produced IFN-γ and eliminated HDV-infected cells via the TRAIL-TRAIL-R2 axis.
  • IFN-β from infected cells enhanced NK cell activity, and NK cells were activated in co-infected patients.

Conclusions:

  • NK cell activation is a feature of HDV infection.
  • NK cells possess the capacity to eliminate HDV-infected hepatocytes through the TRAIL/TRAIL-R2 pathway.
  • NK cells represent a promising target for developing new antiviral therapies for HBV/HDV co-infection.
Abstract

Keywords:
HBVHDVIFN-betaNK cellsTRAIL

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