Identification of woodchuck toll-like receptors and their expression during the course of hepadnaviral infection in the woodchuck model of hepatitis B

Williams, John Bradley (2017) Identification of woodchuck toll-like receptors and their expression during the course of hepadnaviral infection in the woodchuck model of hepatitis B. Masters thesis, Memorial University of Newfoundland.

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Abstract

The woodchuck hepatitis virus (WHV) is closely related to human hepatitis B virus (HBV), the prototypic member of the Hepanaviridae family. Toll-like receptors (TLRs) may play an important role in the pathogenesis of hepadnaviral hepatitis, however, little is known about their expression during the course of hepadnaviral infection. In this study, woodchuck TLRs1-10 gene exon fragments were identified and their transcriptional profiles investigated in livers, hepatocytes isolated from these livers, and peripheral blood mononuclear cells (PBMCs) from healthy woodchucks and animals with different stages of experimental WHV infection. Overall expression analysis revealed that livers from woodchucks with acute hepatitis (AH) and chronic hepatitis (CH) had significantly upregulated expression of TLRs2-10 when compared to the livers of healthy animals and those with self-limited acute hepatitis (SLAH) and primary occult infection (POI). This was likely due to intrahepatic immune cell infiltration. In contrast, a significant downregulation of TLR3, TLR5, TLR7, TLR8, and TLR10 expression was identified in hepatocytes of woodchucks with CH when compared to hepatocytes from healthy animals and those with pre-acute hepatitis (PreAH), SLAH and POI. This may suggest WHV active suppression of the innate immune response in these cells. Upregulated transcription of the majority of TLRs was found in PBMCs during CH but not in other stages of infection. In summary, this study uncovered that TLR expression is significantly modulated depending on the stage of WHV infection and form of hepatitis. Treatments designed to restore hepatocyte TLR expression may allow for better control of the virus through activation of a stronger intrahepatocyte immune response during CH.

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