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Published on: July 6, 2013
Cytomegalovirus infection, viral DNA, and immediate early-1 gene expression in rejecting rat liver allografts
T J Martelius1, M J Blok, K A Inkinen
1Department of Surgery, Helsinki University Hospital, Finland.
Background:
Cytomegalovirus (CMV) infection has been linked to acute and chronic rejection. We have previously shown that concomitant rat cytomegalovirus (RCMV) infection increases portal inflammation and bile duct destruction in rejecting rat liver allografts. Many of the pro-inflammatory effects of CMV have been attributed to the immediate early (IE) proteins of CMV. We wanted to investigate whether RCMV and IE-1 gene expression persist in the liver graft in our model.
Methods:
Liver transplantations were performed from PVG (RT1c) into BN (RT1n) rats. One day after transplantation, the rats were infected with RCMV. No immunosuppression was given. The graft infection was studied by viral culture, immunofluorescence, DNA in situ hybridization and RT-PCR for the detection of IE-1 mRNA at various time points.
Results:
RCMV caused an active infection from 5 days to 2 weeks after transplantation, during which infectious virus was found in the graft. Thereafter the cultures were negative. RCMV antigens and DNA were found in hepatocytes, endothelial, inflammatory, and bile duct cells during the active infection. At 4 weeks, RCMV DNA positive hepatocytes, endothelial, inflamma tory, and bile duct cells could still be found, but in much smaller quantities. IE-1 mRNA expression was, however, only detected during the active infection, not at 4 weeks postinfection.
Conclusions:
RCMV IE-1 expression does not persist in the graft after the active infection, although some viral DNA can be detected in the graft up to 4 weeks. In our model, the CMV-induced increase in graft damage does not seem to require the continued expression of IE-1.
Insights
Rat cytomegalovirus (RCMV) infection causes active inflammation in liver allografts. However, RCMV IE-1 gene expression does not persist after the active infection, suggesting it may not drive long-term graft damage.
Area of Science:
- Transplantation immunology
- Virology
- Graft rejection
Background:
- Cytomegalovirus (CMV) infection is associated with acute and chronic transplant rejection.
- Rat cytomegalovirus (RCMV) exacerbates liver allograft damage, particularly portal inflammation and bile duct injury.
- CMV immediate-early (IE) proteins are implicated in pro-inflammatory responses.
Purpose of the Study:
- To determine if RCMV infection and IE-1 gene expression persist in rat liver allografts.
- To investigate the role of IE-1 in RCMV-induced graft damage.
Main Methods:
- Liver transplantation from PVG to BN rats without immunosuppression.
- Post-transplant RCMV infection.
- Detection of RCMV viral culture, antigens, DNA, and IE-1 mRNA in grafts at various time points.
Main Results:
- RCMV caused active infection in liver grafts from 5 days to 2 weeks post-transplant.
- RCMV antigens and DNA were detected in various graft cells during active infection and at lower levels up to 4 weeks.
- IE-1 mRNA expression was only observed during the active infection phase, not at 4 weeks.
Conclusions:
- RCMV IE-1 gene expression is transient and does not persist in the liver graft after the acute infection phase.
- While viral DNA is detectable up to 4 weeks, sustained IE-1 expression is not required for CMV-induced graft damage in this model.
