title: Suppression of adenoviral gene expression in the liver: role of innate vs adaptive immunity and their cell lysis mechanisms.
abstract: BACKGROUND
  Injection of adenoviral constructs causes liver infection prompting immunity, which suppress viral gene expression. Innate and adaptive immunity mediate these processes raising the question which pathways are the most prominent.
  
  
  METHODS
  Adenovirus expressing the beta-galactosidase (beta-gal) gene was injected into normal and immunodeficient mice. Elimination of beta-gal-expressing hepatocytes and increases in liver enzymes were assayed. Major histocompatibility complex (MHC) class I densities, perforin channel insertion and apoptosis by Fas and tumor necrosis factor (TNF)-alpha were assayed.
  
  
  RESULTS
  At high virus doses, suppression of viral gene expression was as efficient in immunodeficient as in normal mice, while at low doses effects of cytotoxic T lymphocytes (CTL) were demonstrable. Despite CTL priming and elimination of infected hepatocytes no liver injury is detected. Hepatocyte MHC I densities were able to trigger CTL granule exocytosis and perforin lysis in vitro but not in vivo. This is we show is because of decreased sensitivity of hepatocytes from infected mice to perforin and increased sensitivity to Fas and TNF-alpha lysis.
  
  
  CONCLUSIONS
  Effector cells of the innate immune system are exceedingly effective in suppressing adenoviral gene expression. Perforin-independent pathways, those mediated by TNF-alpha and Fas are very efficient in hepatocytes from virus-infected livers.
authors.affiliation: Department of Molecular Microbiology and Immunology, USC/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90033-0800, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Minagawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kawamura
authors.forename: Zhangxu
authors.initials: Z
authors.lastname: Liu
authors.forename: Sugantha
authors.initials: S
authors.lastname: Govindarajan
authors.forename: Gunther
authors.initials: G
authors.lastname: Dennert
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D006525:Hepatitis, Viral, Human / Q000276:immunology* / Q000821:virology*; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018398:Homeodomain Proteins / Q000235:genetics; D008099:Liver / Q000276:immunology / Q000821:virology; D008113:Liver Neoplasms; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin; C064658:RAG-1 protein