Disruption of Rho GTPase Prenylation by Statins Inhibits Respiratory Syncytial Virus
Notice bibliographique
Résumé
INTRODUCTION Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections necessitating hospitalization in the pediatric population. Despite the significant healthcare burden associated with RSV, few options are available to prevent or treat infection. To address the lack of therapeutic strategies for RSV, we developed a high content screening platform to identify small molecule inhibitors of the virus. Following a screen of 2400 compounds, statins were found to significantly reduce RSV infection rates. Here we show that statin‐mediated disruption of isoprenoid biosynthesis and Rho GTPase prenylation blocks late events within the life cycle of RSV, including protein trafficking and viral assembly. METHODS To screen for inhibitors of RSV, human laryngeal epidermoid carcinoma (HEp‐2) cells were infected with recombinant RSV engineered to express green fluorescent protein (GFP). Automated image analysis algorithms were used to quantify infection rate by measuring the proportion of GFP‐fluorescent cells. Statin‐induced changes to the life cycle of RSV were determined by immunofluorescence microscopy and temporal quantification of viral fusion and nucleoproteins. Effects on protein prenylation by statins and RSV were evaluated via click chemistry using azide‐modified isoprenoids with a biotin‐alkyne detection reagent. Rho GTPase activity was quantified by Western blot following affinity purification of active, GTP‐bound RhoA or Rac1. RESULTS Inhibition of RSV by statins was dose‐dependent with an effective concentration (EC50) of 1 μM. Viral events occurring >12 hours post‐infection, including protein trafficking and assembly, were inhibited by statins, whereas early events, such as viral entry, were unaffected. Viral trafficking and assembly are thought to be mediated by Rho GTPases, a group of prenylated proteins which modulate dynamics of the actin cytoskeleton. We found that RhoA‐specific inhibition by Rhosin (50 μM) moderately reduced RSV infection rate (26 ± 6% reduction), but Rac1‐specific inhibition by EHT1864 (20 μM) elicited a profound effect (90 ± 2% reduction). Critically, RSV infection promoted Rac1 prenylation and activity, while statin treatment blocked Rac1 prenylation and reduced active, GTP‐bound protein by 2.5‐fold. CONCLUSIONS Our results demonstrate the importance of protein prenylation to RSV infection and perturbation of this process by statins. Inhibition of Rac1 prenylation and activity by statins serves to block viral protein trafficking and assembly. Based on our findings, we propose repurposing statins as a treatment for RSV as these drugs potently inhibit the virus, are US Food and Drug Administration approved and have favorable clinical safety profiles. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 ».