4.5 Article

TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection

Journal

JHEP REPORTS
Volume 2, Issue 3, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.jhepr.2020.100098

Keywords

HDV; liver injury; TNF-alpha; Etanercept; Antigens; Hepatitis Delta virus; Hepatitis B

Funding

  1. Secretaria de Estado de Investigacion, Desarrollo e Innovacion, Ministerio de Economia y Competitividad [SAF2015-70028-R, RTI2018-101936-B-I00]
  2. Ministerio de Ciencia y tecnologia
  3. Spanish Ministry of Education
  4. Spanish Ministry of Economy and Competitiveness
  5. FIMA fellowship

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Background & Aims: HDV infection induces the most severe form of human viral hepatitis. However, the specific reasons for the severity of the disease remain unknown. Recently, we developed an HDV replication mouse model in which, for the first time, liver damage was detected. Methods: HDV and HBV replication-competent genomes and HDV antigens were delivered to mouse hepatocytes using adeno-associated vectors (AAVs). Aminotransferase elevation, liver histopathology, and hepatocyte death were evaluated and the immune infiltrate was characterized. Liver transcriptomic analysis was performed. Mice deficient for different cellular and molecular components of the immune system, as well as depletion and inhibition studies, were employed to elucidate the causes of HDV-mediated liver damage. Results: AAV-mediated HBV/HDV coinfection caused hepatocyte necrosis and apoptosis. Activated T lymphocytes, natural killer cells, and proinflammatory macrophages accounted for the majority of the inflammatory infiltrate. However, depletion studies and the use of different knockout mice indicated that neither T cells, natural killer cells nor macrophages were necessary for HDV-induced liver damage. Transcriptomic analysis revealed a strong activation of type I and II interferon (IFN) and tumor necrosis factor (TNF)-alpha pathways in HBV/HDV-coinfected mice. While the absence of IFN signaling had no effect, the use of a TNF-alpha antagonist resulted in a significant reduction of HDV-associated liver injury. Furthermore, hepatic expression of HDAg resulted in the induction of severe liver damage, which was T cell- and TNF-alpha-independent. Conclusions: Both host (TNF-alpha) and viral (HDV antigens) factors play a relevant role in HDV-induced liver damage. Importantly, pharmacological inhibition of TNF-alpha may offer an attractive strategy to aid control of HDV-induced acute liver damage. (C) 2020 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).

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