Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction.
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 shown that the host CD4(+) T-cell response to CMV antigen can produce IFNgamma and TNFalpha at levels sufficient to drive induction of fractalkine, a key marker of inflammation in endothelial cells. We have also observed a major pathogenic effect in which endothelial cell damage and loss follow the induction of fractalkine and up-regulation 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-CX(3)CR1 interaction resulting in recruitment of natural killer (NK) cells and monocyte-macrophages plays an important role in mediating this endothelial damage. Supportive evidence for frac-talkine's key role is shown by the ability of specific antibody to CX(3)CR1 to reduce significantly CX(3)CR1(+)-bearing cell chemoattraction and to protect against endothelial damage. These findings support CMV as a member of a class of persistent pathogens in which a high T-cell response and chemokine-mediated effects are a risk factor for development of chronic inflammation and endothelial cell injury.
Bolovan-Fritts
Cynthia A
CA
Department of Pediatrics, Division of Infectious Diseases, University of California San Diego, La Jolla, CA 92093-0672, USA.
Spector
Stephen A
SA
D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology / Q000494:pharmacology; D000956:Antigens, Viral / Q000276:immunology / Q000494:pharmacology; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D018920:Coculture Techniques; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D019707:Receptors, Chemokine / Q000378:metabolism*
D000914:Antibodies, Viral; D000956:Antigens, Viral; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D018950:Lipopolysaccharide Receptors; D019707:Receptors, Chemokine