Cryo-EM of an Anti-enterovirus Cross Species Neutralizing Antibody
Notice bibliographique
Résumé
Enteroviruses (EVs) are common and ubiquitous human pathogens. This genus includes poliovirus, echoviruses, Coxackieviruses A and B, EVs A and D, as well as human rhinovirus (HRV). These single stranded (+) RNA viruses can cause a broad spectrum of serious illness. Infection with these pathogens is known to elicit the production of cross-reactive antibodies to other species of enteroviruses. The significance of these cross-reactive antibodies to antiviral immunity is not well understood. These antibodies are assumed not to neutralize infection as they are thought to recognize shared epitopes that are only exposed when the conformation of the virion is perturbed [1]. Using plaque reduction and enzyme-linked immunosorbent assay (ELISA)-based binding assays, we determined that cross-species anti-EV monospecific polyclonal sera can block infection of cells in culture by a heterologous EV. As polyclonal sera are mixtures of hundreds, if not thousands, of individual mAbs, we performed plaque reduction assays using site specific anti-poliovirus P1/Mahoney mAbs. To determine if known antipoliovirus site-specific mAbs can bind heterologous EVs, murine monoclonal site specific antipoliovirus antibodies were incubated with multiple EVs. The poliovirus mAb that binds the border of two adjacent pentamers, at the three-fold symmetry axis (site 4), interacted with HRV-A1A, multiple isolates of EV-D68, EV-A71 and echovirus 29 while antibodies that recognizes site 2 bound EV-A71 and HRV-A1A but no isolate of EV-D68 tested. Furthermore, mAbs against site 4 of poliovirus were able to protect cells in culture from infection with HRV-A1A. We used cryo-electron microscopy (cryo-EM) to determine the structure of this cross-species neutralizing antibody as a fAb bound to Mahoney strain poliovirus (serotype 1). With our high-resolution cryo-EM map, we used an automated atomic model building tool, Modelangelo [2], to produce an atomic model of the bound fAb which describes the interaction of this cross-reactive antibody bound to poliovirus. We believe this cross-reactive antibody neutralizes infection by stabilizing capsid conformation, thus preventing genome translocation. We will compare the interface this cross-species neutralizing antibody forms with poliovirus and HRV-A1A. The results from this study will provide further insight into the antigenic relationship of EVs and mechanisms of antibody mediated protection. (A) Cryo-EM density map of poliovirus bound by cross-species neutralizing antibody (gray). (B) Surface representation of cross-species neutralizing fAb atomic model (violet). (C) This cross-species neutralizing antibody binds the three-fold axis of the poliovirus capsid, interfacing with VP2 (yellow) and VP3 (red). (D) Surface representation of the previously described crystal structure of Mahoney strain poliovirus (1HXS) [3] fit within our cryo-EM density map. Viral proteins are colored by radial distance from the center of the capsid. (A) Cross-species neutralizing antibody atomic model and the previously described crystal structure of Mahoney strain poliovirus (1HXS) fit within our cryo-EM density map, color coded to depict the distance between capsid and fAb residues. (B) Close up of color-coded atomic models and cryo-EM density map within box of panel A. (C) Capsid proteins are labeled to show that the interface between fAb and Mahoney strain poliovirus is formed between two copies of VP2 and one copy of VP3.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,001 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 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 ».