Granulocyte-mediated injury to herpes simplex virus-infected human endothelium

Some endothelial-injury syndromes, including atherosclerosis, may involve herpes simplex virus (HSV) infection. Examining the mechanism of injury, we found adherence of unstimulated granulocytes to HSV infected endothelium to be twice that to uninfected endothelium (34.8 ± 1.1 versus 18.8 ± 0.5%; mean ± SEM; p < 0.001) which further increased in the presence of anti-HSV antibodies. Enhanced adhesion was accompanied by excessive granulocyte-mediated lysis of ⁵¹Cr-labeled, HSV-infected endothelium (16.4 ± 0.9%, HSV-infected versus 0.9 ± 4.5% for uninfected endothelium; p < 0.01). HSV infection also increased granulocyte-mediated endothelial cell detachment from its substratum (14.7 ± 1.7% versus 3.3 ± 0.3% for uninfected endothelium; p < 0.001), which further increased (p < 0.01) in the presence of immune complexes (IgG-sensitized erythrocytes). This suggests that neo-Fc receptors of infected endothelium bind IgG-coated particles, which, in turn, attract and stimulate granulocytes. In support, granulocyte-mediated detachment was not enhanced by immune complexes if endothelium was infected with a mutant HSV strain (E3/3) that does not produce glycoprotein E, the viral glycoprotein having Fc-receptor activity. Exaggerated endothelial detachment correlated with poor binding of infected endothelial cells to the substratum matrix protein, fibronectin. Resuspended, virus-infected endothelial cells bound significantly less well to tissue-culture wells coated with both low (p < 0.001) and high (p < 0.05) concentrations of fibronectin as compared with uninfected endothelial cells, a dichotomy further worsened in the presence of granulocyte-released elastase. We conclude that HSV-infected human endothelium is vulnerable to granulocyte-mediated injury by opposing alterations in its adhesive properties: its increased binding of granulocytes and its weakened tethering to matrix fibronectin, particularly when exposed to secreted granulocyte proteases, such as elastase.