Reovirus genomic diversity confers plasticity for protease utility during adaptation to intracellular uncoating
Notice bibliographique
Résumé
ABSTRACT Mammalian orthoreoviruses (reoviruses) infect many mammals and provide a safe model to study enteric viruses. Knowledge of reoviruses is derived from prototypic lab strains, notably T1L and T3D. Based on these prototypic strains, reoviruses can efficiently utilize gut or lysosomal proteases for uncoating and penetration into host cytoplasm. To discover natural reovirus characteristics, we isolated four genetically diverse wastewater reovirus samples and compared their genetic and phenotypic characteristics to those of T1L/T3D. On L929 cells, the most commonly used model for reovirus studies, naturally derived reoviruses displayed lower fitness than T1L/T3D, evident from smaller plaques and higher relative particle-to-PFU ratios. In contrast to T1L/T3D, which are uncoated efficiently by lysosomal-mediated proteolysis, naturally derived reoviruses displayed poor uncoating kinetics. Exposure of naturally derived reoviruses to gut proteases led to rapid extracellular uncoating and significantly improved infectivity relative to T1L/T3D, indicating that wild reoviruses depended more on extracellular gut proteases. To discover if reovirus can adapt to new host proteases, naturally derived samples were passaged on L929 cells, and large and small plaque-forming isolates were evaluated. Larger plaque sizes correlate with faster intracellular uncoating. Whole-genome sequencing identified the outer capsid σ3 protein as the determinant of uncoating proficiency between wild reoviruses. Interestingly, mutations that permitted intracellular uncoating were found in 0.01% of the parental quasispecies, suggesting that variants with altered protease sensitivity were rapidly selected for during cell culture propagation. Altogether, these findings indicate that naturally circulating reoviruses are more reliant on gut proteases, but the genetic diversity of reovirus quasispecies bestows tremendous plasticity toward protease utility. IMPORTANCE Reoviruses infect many mammals and are widely studied as a model system for enteric viruses. However, most of our reovirus knowledge comes from laboratory strains maintained on immortalized L929 cells. Herein, we asked whether naturally circulating reoviruses possess the same genetic and phenotypic characteristics as laboratory strains. Naturally circulating reoviruses obtained from sewage were extremely diverse genetically. Moreover, sewage reoviruses exhibited poor fitness on L929 cells and relied heavily on gut proteases for viral uncoating and productive infection compared to laboratory strains. We then examined how naturally circulating reoviruses might adapt to cell culture conditions. Within three passages, virus isolates from the parental sewage population were selected, displaying improved fitness and intracellular uncoating in L929 cells. Remarkably, selected progeny clones were present at 0.01% of the parental population. Altogether, using reovirus as a model, our study demonstrates how the high genetic diversity of naturally circulating viruses results in rapid adaptation to new environments.
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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 | 0,000 |
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 ».