Suppression of adenoviral gene expression in the liver: role of innate vs adaptive immunity and their cell lysis mechanisms
Article first published online: 20 MAY 2005
Volume 25, Issue 3, pages 622–632, June 2005
How to Cite
Minagawa, M., Kawamura, H., Liu, Z., Govindarajan, S. and Dennert, G. (2005), Suppression of adenoviral gene expression in the liver: role of innate vs adaptive immunity and their cell lysis mechanisms. Liver International, 25: 622–632. doi: 10.1111/j.1478-3231.2005.01097.x
- Issue published online: 20 MAY 2005
- Article first published online: 20 MAY 2005
- Received 7 June 2004, accepted 19 September 2004
- innate immunity;
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 β-galactosidase (β-gal) gene was injected into normal and immunodeficient mice. Elimination of β-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)-α 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-α lysis.
Conclusion: Effector cells of the innate immune system are exceedingly effective in suppressing adenoviral gene expression. Perforin-independent pathways, those mediated by TNF-α and Fas are very efficient in hepatocytes from virus-infected livers.