Herpesviruses Enhance Fibrinogen Clot Lysis.
Notice bibliographique
Résumé
Abstract Abstract 1153 Background: Members of the Herpesvirus family have been implicated in vascular disease. To explain the correlation on a molecular basis we have shown that the virus envelope contains anionic phospholipid derived from host cells, and proteins encoded by the host (tissue factor) as well as the viral (glycoprotein C) genomes, which initiate blood coagulation. This suggests that virus infection should be a strong independent predictor of vascular disease. Nevertheless, the clinical correlation is relatively weak, becoming more significant in combination with other risk factors. To explain this discrepancy, the current work is based on our additional report that at least one Herpesvirus (cytomegalovirus (CMV)) has host-genome-encoded annexin II on its surface. Annexin II is known to accelerate tissue plasminogen activator (tPA)-mediated activation of plasminogen to plasmin because of C-terminal lysines that interact with both plasminogen and tPA. Plasmin is the primary fibrinolytic protease, and is necessary for physiological clot dissolution. Thus, these viruses may facilitate clearance of the fibrin they generate. Hypothesis: We hypothesize that Herpesviruses enhance tPA-mediated plasmin generation and this mechanism correlates to the presence of annexin II on the virus. Methods: Purified herpes simplex virus type 1 (HSV1) and 2 (HSV2) and CMV were quantified by electron microscopy. Annexin II expression varies between cell types, therefore HSV1 was propagated in several cell lines. Virus-dependent plasmin generation was followed in the presence of purified plasminogen and tPA using a chromogenic assay. The contribution of viruses to fibrin clot lysis using purified proteins was investigated by light scattering. Plasminogen-conjugated horse radish peroxidase (plasminogen-HRP) and western blots were used to identify plasminogen-binding species and annexin II associated with the virus, respectively. The effect of plasmin-mediated signalling on virus infection was determined using cytopathic plaque assays. Results: Chromogenic experiments demonstrated that HSV1, HSV2 and CMV enhanced plasminogen activation in a dose-dependent manner by up to 5-fold, regardless of the parental cell line. Prolonged incubation confirmed the requirement for exogenous tPA. Plasminogen-HRP bound to a number of virus-associated proteins and was shown to be C-terminal lysine-dependent by complete inhibition with epsilon-aminocaproic acid (EACA). Annexin II was demonstrated to be associated with purified HSV1 cultured in different cells except when propagated in a melanoma (A7) line that did not express annexin II. An annexin II antibody inhibited binding of plasminogen-HRP to viral annexin II. HSV1, HSV2 and CMV accelerated fibrin clot lysis, which was inhibited in the presence of EACA and aprotinin, a plasmin inhibitor. However, in contrast to the chromogenic experiment for plasmin generation, each virus also exhibited a clot lysis mechanism independent of added tPA. As we have previously identified for thrombin, incubation of host cells with purified plasmin during inoculation enhanced virus infection by over 3-fold. Conclusion: Cumulatively these data demonstrate that HSV1, HSV2 and CMV accelerate tPA- mediated plasmin generation in the absence of fibrin and identify annexin II as one of several plasminogen binding partners. These viruses furthermore enhance the rate of fibrin clot lysis. However, in the presence of fibrin, purified HSV1, HSV2 and CMV are capable of facilitating clot dissolution in the absence of exogenous tPA. The molecular basis for this novel mechanism is not yet known, but requires plasminogen activation. The finding that purified plasmin enhances infection suggests these viruses may have evolved to initiate plasmin generation. Hence, the virus-mediated activation of fibrinolysis may compensate for its ability to trigger coagulation and attenuate potential contributions as an independent predictor of vascular disease. Disclosures: No relevant conflicts of interest to declare.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».