Herpes Simplex Virus Infection of Endothelial Cells Is Enhanced by Thrombin.
Notice bibliographique
Résumé
Abstract Herpes simplex virus type 1 (HSV1) and type 2 (HSV2) are highly prevalent and form life-long infections. While acute effects are not often critical, chronic infection has been linked to vascular disease. To better understand the underlying basis for the clinical correlations, our lab has demonstrated that HSV can initiate and sustain clot formation directly on the virus surface, bypassing the normal cellular requirements. This is facilitated by anionic phospholipid and tissue factor on HSV1 and HSV2, and the participation of at least HSV1- encoded glycoprotein C (gC) in factor VIIa-dependent factor X (FX) activation, emulating tissue factor. The evolution of the HSV surface as a procoagulant agent suggests that generation of thrombin is advantageous to the viral lifecycle. The current study therefore examines the hypothesis that thrombin enhances infection. Several purified HSV1 strains were evaluated, including the wild-type lab strain, MacIntyre, and the clinical isolate, NS. These viruses were compared to gC-deficient HSV1, ns-1, and the gC-restored strain, rns. As an example of HSV2, strain G, was also examined. ns-1 has been shown previously to generate less FXa per particle than the gC-containing viruses. To restrict in situ thrombin production, human umbilical vein endothelial cells were inoculated in serum-free culture media. Consistent with our hypothesis, standard plaque-forming assays revealed that co-incubation of the virus and cells with purified thrombin enhanced infection by up to 400%. The observed half-maximal concentration was approximately 20 nM thrombin for all viruses studied. As a demonstration of specificity, hirudin attenuated the effects of purified thrombin. The involvement of the protease activated receptor 1 (PAR1) in this mechanism was shown using the functional signaling analogue, thrombin receptor activating peptide (TRAP). In the absence of serum, TRAP resulted in increased infection comparable to that of purified thrombin. Approximately half the effect of TRAP was observed at 10uM, while a PAR4-activating peptide had no effect. Enabling the production of thrombin during the infection process, plaque-forming assays were also conducted with serum in the cell culture media. The presence of serum enhanced infectivity by as much as 20-fold. At a constant hirudin concentration of 5 U/ml, infection was attenuated by approximately 50% for the gC-deficient strain, ns-1, whereas the other viruses were only marginally or insignificantly affected, supporting a role for thrombin generation in situ and the participation of gC. Collectively, these data show that thrombin production by HSV enhances infection through a mechanism involving PAR1-mediated cell modulation.
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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 | 0,001 | 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) | 0,002 | 0,000 |
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 ».