| Summary: | Vascular disease, a leading cause of death worldwide, is associated with multiple risk factors that include age, diet, lifestyle and genetics. Herpesviruses, highly prevalent in the general population, have also been linked to vascular disease. To investigate the molecular basis of this relationship, the interactions between virus surface proteins and host hemostatic plasma proteins, comprising both clot forming (coagulation) and clot dissolving (fibrinolytic) proteases, which can both contribute to vascular disease, were studied.
Previously, our laboratory demonstrated that purified herpes simplex virus type-1 (HSV1) and -2 (HSV2) and cytomegalovirus (CMV) contain cell-derived tissue factor (TF) and anionic phospholipids (aPL). Independent of cells, TF and aPL with factor (F) VIIa (FVIIa) initiate the extrinsic pathway of coagulation, activate FX to FXa, and lead to thrombin generation. This thesis identified additional herpesvirus-mediated coagulation pathway(s) and also demonstrated herpesvirus-mediated fibrinolysis.
In addition to TF, FVIII amplified HSV1-initiated coagulation through the intrinsic pathway. Alternatively, independent of TF, HSV1 initiated coagulation through the contact pathway, via FXII activation. The ability to exploit the extrinsic, intrinsic and contact pathway of coagulation should make herpesvirus infection a strong prothrombotic risk yet the clinical correlation to vascular disease is relatively weak.
To explain the in vitro versus clinical discrepancy, virus-mediated fibrinolysis was evaluated. Purified herpesviruses accelerated tissue plasminogen activator (tPA)-dependent plasminogen (Pg) activation to plasmin (Pn), the primary fibrinolytic protease responsible for fibrin clot dissolution. This Pn generation was independent of the physiological cofactor fibrin. Cell-derived annexin 2 (A2), previously identified on the surface of CMV, is a known accelerator of tPA-dependent Pn generation. Although A2 was identified among several Pg binding partners associated with each herpesvirus, it was dispensable for Pn generation. Herpesvirus-mediated plasminogen activation enhanced fibrinolysis independent of exogenous tPA. The enhanced fibrinolysis may attenuate the prothrombotic risk of herpesviruses, as an independent predictor of vascular disease. Plasmin enhanced cell susceptibility to infection, a virus-survival advantage also known for thrombin, FVIIa and FXa.
Overall, for herpesviruses and other enveloped viruses, a mechanism is suggested where the envelope constituents initiate the activation of both pro-coagulation and pro-fibrinolytic proteins, modulating host cell susceptibility to infection and contributing to vascular disease.
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