Submitted August 21, 2007
Accepted September 18, 2007
Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction
Cynthia A. Bolovan-Fritts and Stephen A Spector*
Department of Pediatrics, Division of Infectious Diseases, Center for Molecular Genetics and Center for AIDS Research, University of California San Diego, La Jolla, CA, United States
* Corresponding author; email: saspector{at}ucsd.edu.
Human cytomegalovirus (CMV) infection has been linked to inflammatory diseases including vascular disease and chronic transplant rejection that involve vascular endothelial damage. We have previously demonstrated that the host CD4+ T-cell response to CMV antigen can produce IFN
and TNF
at levels sufficient to drive induction of fractalkine, a key marker of inflammation in endothelial cells. We have also observed a major pathogenic effect where endothelial cell damage and loss follow the induction of fractalkine and upregulation of cell adhesion markers in the presence of peripheral blood mononuclear cells (PBMCs) from donors with a high CMV-specific T cell frequency. In this report, we show that the fractalkine-CX3CR1 interaction resulting in recruitment of NK cells and monocyte-macrophages plays an important role in mediating this endothelial damage. Supportive evidence for fractalkine's key role is demonstrated by the ability of specific antibody to CX3CR1 to reduce significantly CX3CR1+ bearing cell chemoattraction and to protect against endothelial damage. These findings support CMV as a member of a class of persistent pathogens where a high T-cell response and chemokine-mediated effects are a risk factor for development of chronic inflammation and endothelial cell injury.
