Characterization of a mouse model for the study of hepatitis delta virus infection
Autor(es) : 
Palabras clave : 
Materias Investigacion::Ciencias de la vida
Virología
Inmunología
Fecha de publicación: 
30-oct-2018
Fecha de la defensa: 
2-jul-2018
Cita: 
USAI, C. "Characterization of a mouse model for the study of hepatitis delta virus infection", González, G. y Aldabe, R. (dirs.). Tesis doctoral. Universidad de Navarra, Pamplona, 2018.
Resumen
Hepatitis delta virus (HDV) is a defective RNA virus that depends on hepatitis B virus (HBV) for the formation of new virions. HDV induces the most severe form of human viral hepatitis with the worst prognosis. However, the specific reasons for the severity of the disease remain unknown. Studying hepatitis delta virus (HDV) and developing new treatments is hampered by the absence of small animal models. Here we describe a robust mouse model of HDV infection that mimics several important characteristics of the human disease. HDV- and HBV-replication competent genomes were delivered to the mouse liver using adeno-associated viruses (AAV) (AAV-HDV and AAVHBV). Viral load, antigen expression and genomes were quantified at different time points after AAV injection. Furthermore, liver pathology, genome editing, and the activation of the innate immune response were evaluated. AAV-HDV infection initiated HDV replication in mouse hepatocytes. Genome-editing was confirmed by the presence of small and large-HDV antigens and sequencing. Viral replication was detected for 45 days, even after the AAV-HDV vector had almost disappeared. In the presence of HBV, HDV infectious particles were detected in serum. Furthermore, as observed in patients, co-infection was associated with the reduction of HBV antigen expression and the onset of liver damage that included the up-regulation of genes involved in the development of liver pathologies. HDV replication induced a sustained type-I IFN response, which was significantly ameliorated in immunodeficient mice and almost absent in MAVS-deficient mice. The animal model described here reproduces important characteristics of human HDV infection and provides a valuable tool for characterizing the viral infection and for developing new treatments. Furthermore, MAVS was identified as a main player in HDV detection and adaptive immunity was found to be involved in the amplification of the innate immune response. A significant liver inflammatory infiltrate were observed in immunocompetent as well in partially immunodeficient strais. Activated T lymphocytes, natural killer cells, dendritic cells and pro-inflammatory macrophages account for the majority of the inflammatory infiltrate and contribute in the hepatic expression of TGF-β, ISG15, ADAR-1, IP10, PKR, and USP18. However, neither T cells, natural killer cells nor macrophages are necessary for the induction of the observed liver damage; on the contrary, our data indicate that macrophages have a protective role early after infection. The role of type I- and type II IFN was also discarded. Moreover, we found that the hepatic expression of the HDV antigens in the absence of active HDV replication is sufficient to induce a dose-dependent liver toxicity.

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Tesis_Usai18.pdf
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