Abstract
Purpose: :
We have shown previously that mice infected systemically with murine cytomegalovirus (MCMV) for 12 weeks (chronic infection) exhibit increased size and severity of experimental choroidal neovascularization (CNV) when compared with animals infected systemically with MCMV for 6 days (acute infection). Although the mechanism is uncertain, we hypothesize that MCMV-mediated activation of macrophages during chronic infection leads to production of VEGF, an event that does not occur during acute infection.
Methods: :
Four groups of C57BL/6 mice were injected intraperitoneally with either a non-lethal dose of MCMV or UV-inactivated virus (control). At 6 days or 12 weeks after inoculation, either splenic cells from whole spleens or populations of splenic macrophages enriched by flow cytometry (~90% purity) were collected from all animal groups and subjected to real time RT-PCR assay for quantification of VEGF and VEGF receptor (VEGF-R) mRNA levels. Presence of infectious virus in whole blood was determined by standard plaque assay.
Results: :
Whereas significantly high amounts of VEGF and VEGF-R mRNA levels were found in splenic cells from chronically infected mice, splenic cells or enriched populations of splenic macrophages from acutely infected mice harbored VEGF and VEGF-R mRNA at levels equivalent to those found in animals injected with UV-inactivated virus. As expected, infectious virus was detected in whole blood from acutely infected animals, but not detected in whole blood from chronically infected animals.
Conclusions: :
We conclude that increased expression of VEGF and VEGF-R by macrophages is a late event that takes place during chronic virus infection but not acute virus infection. This conclusion would help to explain the increase in size and severity of experimental CNV observed in chronically infected mice when compared with acutely infected mice. The precise time during the course of systemic MCMV infection at which macrophages become activated to produce large amounts of VEGF remains to be determined. We predict that administration of the antiviral drug ganciclovir during chronic infection will not decrease VEGF production by MCMV-activated macrophages.
Keywords: cytomegalovirus • choroid: neovascularization • vascular endothelial growth factor