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STUDIES OF HEPATITIS B VIRUS AND HEPATITIS C VIRUS IN SCID/BEIGE-ALB/UPA CHIMERIC MICE

  • Author / Creator
    Chen, Ran
  • Both hepatitis C virus (HCV) and hepatitis B virus (HBV) infections represent major global public health problems. Interferon (IFN) has been an important factor in both resolution of infection and in the treatment of both infections. Clinical data on anti-HBV and anti-HCV innate immune responses, in particular the IFN response, during natural infection in patients are limited. This is, in part, because most of patients are asymptomatic during acute stages of infection. IFN has been used to treat both HBV and HCV infections for years. Unfortunately, many patients do not respond to the IFN therapy. The reason for the variable treatment outcomes, in particular, the nonresponsiveness to IFN therapy in both HBV and HCV infections still remains unclear. In this thesis, IFN responses in HBV and HCV infections were studied using the severe combined immunodeficiency (SCID) / beige (bg) - albumin (Alb) / urokinase-type plasminogen activator (uPA) chimeric mouse model. The SCID/bg-Alb/uPA chimeric mouse model was initially reported in 2001. This model supports robust and sustained infection by clinical or tissue culture derived hepatitis viruses, such as hepatitis A virus (HAV), HBV and HCV. Evidence has shown that the antiviral response to IFN in the chimeric mouse often reflects closely the response of the identical virus in humans when treated with IFN. A time course of HCV infection was performed in SCID/bg-Alb/uPA chimeric mice to study an induced endogenous IFN response. There was a peak of interferon-stimulated gene (ISG) response at day-10 post infection, but no significant ISG upregulation was observed in long-term HCV infection in the mice. I also investigated the contributions of viral and host factors on the response of HCV infection to IFN treatment using two HCV viral strains differing in their IFN-sensitivity. These studies were performed in chimeric mice produced using three hepatocyte donors, each with distinct interleukin (IL) 28B single nucleotide polymorphisms (SNPs) at both rs12979860 and rs8099917 loci. My results showed that virus factors were the key factors determining the outcome of IFN therapy, whereas, viral interference with host janus kinase - signal transducer and activator of transcription (JAK-STAT) pathway as well as host factors, such as polymorphisms at the IL28B loci and pre-treatment levels of intrahepatic ISG expression, were less important in determining the outcome of IFN therapy in chimeric mice than they are in the patients. In addition, endogenous IFN response during the course of HBV in the SCID/bg- Alb/uPA chimeric mice was examined. No significant IFN or ISG response was detected in chimeric mice during the course of HBV infection. Since both the HBV and HCV viruses used in my studies were nonresponsive to exogenous IFN treatment in chimeric mice, the molecular mechanism of IFN nonresponsiveness of the two viruses was compared in a cohort of donor-matched chimeric mice. I found that in HBV infected chimeric mice, but not in mice infected with HCV, the JAK-STAT pathway was inhibited by STAT1 nucleus translocation blockage and thus expression downregulation of ISGs in response to exogenous IFN treatment. Finally, two collaborative projects were completed during my PhD. In the first study, the potential antiviral activity of exogenous HCV pathogen-associated molecular pattern (PAMP) RNA was investigated in HCV-infected SCID/bg- Alb/uPA chimeric mice. My results suggested that HCV PAMP RNA administration elicited an innate immune response in the livers of chimeric mice, which limited HCV infection. In the second study, we found that HCV infection in chimeric mice enhanced microRNA-27 expression and resulted in upregulating hepatic lipid droplet (LD) biogenesis. These results represented a novel mechanism by which HCV induces steatosis in chronic carriers of HCV.

  • Subjects / Keywords
  • Graduation date
    2014-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3XK84Z5R
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Medical Microbiology and Immunology
  • Specialization
    • Virology
  • Supervisor / co-supervisor and their department(s)
    • Dr. Tyrrell, Lorne (Medical Microbiology and Immunology)
  • Examining committee members and their departments
    • Dr. Tyrrell, Lorne (Medical Microbiology and Immunology)
    • Dr. Schang, Luis (Department of Biochemistry)
    • Dr. Liu, Qiang (Vaccine and Infectious Disease Organization, University of Saskatchewan)
    • Dr. Kane, Kevin (Medical Microbiology and Immunology)
    • Dr. Foley, Edan (Medical Microbiology and Immunology)