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

Carla Usai; Sheila Maestro; Gracian Camps; Cristina Olague; Lester Suárez-Amaran; Africa Vales; Tomas Aragon; Mirja Hommel; Rafael Aldabe; Gloria Gonzalez-Aseguinolaza

doi:10.1016/j.jhepr.2020.100098

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

JHEP Rep. 2020 Mar 10;2(3):100098. doi: 10.1016/j.jhepr.2020.100098. eCollection 2020 Jun.

Affiliation

¹ Gene Therapy and Regulation of Gene Expression Program, CIMA, University of Navarra, Instituto de Investigacion Sanitaria de Navarra, IdisNA, Pamplona, Spain.

Abstract

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)-α pathways in HBV/HDV-coinfected mice. While the absence of IFN signaling had no effect, the use of a TNF-α 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-α-independent.

Conclusions: Both host (TNF-α) and viral (HDV antigens) factors play a relevant role in HDV-induced liver damage. Importantly, pharmacological inhibition of TNF-α may offer an attractive strategy to aid control of HDV-induced acute liver damage.

Lay summary: Chronic hepatitis delta constitutes the most severe form of viral hepatitis. There is limited data on the mechanism involved in hepatitis delta virus (HDV)-induced liver pathology. Our data indicate that a cytokine (TNF-α) and HDV antigens play a relevant role in HDV-induced liver damage.

Keywords: AAT, alpha-1-antitrypsin; AAV, adeno-associated virus; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Antigens; EAlb, albumin enhancer; Etanercept; HCC, hepatocellular carcinoma; HDV; Hepatitis B; Hepatitis Delta virus; IFN, interferon; IHC, immunohistochemistry; IHL, Intrahepatic leukocytes; KO, knockout; L-HDAg, large hepatitis D antigen; MAIT, mucosal-associated invariant T cells; MAVS, mitochondrial antiviral signaling protein; NK, natural killer; NKT, natural killer T; Rag1, recombination activating gene 1; S-HDAg, short hepatitis D antigen; TNF, tumor necrosis factor; TNF-α; Tg, transgenic; ULN, upper limit of normal; dpi, days post infection; liver injury.