Novel pathogenic mechanisms of porcine reproductive and respiratory syndrome virus: intercellular transmission and persistence
Notice bibliographique
Résumé
Porcine reproductive and respiratory syndrome virus (PRRSV) causes a tremendous economic loss in swine industry worldwide.The capabilities to evade host immune responses and to establish persistent infection are the two hallmark features of PRRSV infection.In this dissertation, the research was mainly focused on investigating the novel mechanisms underlying PRRSV transmission and persistence.In chapter 2, the research was focused on an alternative pathway of PRRSV intercellular transmission.Our data showed that intercellular nanotube connections can be utilized for cell-tocell spreading the core infectious viral machinery (viral RNA, certain replicases and structural proteins) of PRRSV.Live-cell movies tracked the intercellular transport of a recombinant PRRSV that expressed green fluorescent protein (GFP)-tagged nsp2 in a receptor-independent manner.The cytoskeleton proteins F-actin and myosin-IIA were identified as co-precipitates with PRRSV nanotube associated proteins.Drugs inhibiting actin polymerization or myosin-IIA activation prevented nanotube formations and viral clusters in virus-infected cells.These data lead us to propose that PRRSV utilizes the host cell cytoskeletal machinery inside nanotubes for efficient cell-to-cell spread.This form of virus transport represents an alternative pathway for virus spread, which is resistant to the host humoral immune response.In chapter 3, we further showed that PRRSV infection could induce the formation of nanotubes between infected and uninfected cells following a ROS-dependent nanotube formation model.Co-culturing PRRSV-infected cells with uninfected cells rescued PRRSV-induced cell death.Mitochondrion was observed transferring from uninfected to PRRSV-infected cells.Importantly, impaired formation of nanotube or defective mitochondrion was unable to rescue infected cells from apoptosis/necrosis.Certain PRRSV proteins were detected to associate with mitochondria and transport from infected to uninfected cells through TNTs.Our results suggest that TNTs-transfer of functional mitochondria rescued PRRSV-infected cells from apoptosis/necrosis in the early stage of infection.On the other hand, mitochondria could be utilized as a cargo to transport viral materials for spreading the infection.In chapter 4, a novel mechanism s of PRRSV persistent infection has been studied.In this study, a cellular model of persistent infection was established.Strand-specific quantitative RT-PCR and RNase I treatment analysis showed that double-stranded RNA (dsRNA) conformation existed in persistently infected cells.This data has been further confirmed in vivo by performing two independent PRRSV persistence studies.Immunohistochemistry analysis showed that viral dsRNAs were detected aggregating inside the germinal centers of tonsils and lymph nodes from PRRSV persistence pigs, but RNA array analysis further showed that dsRNA in lymphoid tissues had limited ability to stimulate host antiviral responses during persistent infection stage.These results suggest that the PRRSV dsRNA functions as a mediator for viral persistence.The viral dsRNA persistence in germinal centers of lymphoid tissues may reveal a novel mechanism for PRRSV to escape antiviral immune responses.In summary, this study investigated two novel pathogenic mechanisms of PRRSV infection, which could provide insights on the development of effective control strategies.
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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 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| 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 ».