Closely related reovirus lab strains induce opposite expression of RIG-I/IFN-dependent versus -independent host genes, via mechanisms of slow replication versus polymorphisms in dsRNA binding σ3 respectively.
Capsid Proteins
/ genetics
Cytokines
Humans
Interferon Regulatory Factor-3
/ genetics
Interferons
/ metabolism
Orthoreovirus, Mammalian
/ physiology
Polymorphism, Genetic
RNA, Double-Stranded
/ genetics
RNA, Viral
/ genetics
RNA-Binding Proteins
/ genetics
Receptors, Retinoic Acid
/ genetics
Reoviridae Infections
/ genetics
Signal Transduction
Virus Replication
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
07
01
2020
accepted:
13
07
2020
revised:
01
10
2020
pubmed:
22
9
2020
medline:
22
10
2020
entrez:
21
9
2020
Statut:
epublish
Résumé
The Dearing isolate of Mammalian orthoreovirus (T3D) is a prominent model of virus-host relationships and a candidate oncolytic virotherapy. Closely related laboratory strains of T3D, originating from the same ancestral T3D isolate, were recently found to exhibit significantly different oncolytic properties. Specifically, the T3DPL strain had faster replication kinetics in a panel of cancer cells and improved tumor regression in an in vivo melanoma model, relative to T3DTD. In this study, we discover that T3DPL and T3DTD also differentially activate host signalling pathways and downstream gene transcription. At equivalent infectious dose, T3DTD induces higher IRF3 phosphorylation and expression of type I IFNs and IFN-stimulated genes (ISGs) than T3DPL. Using mono-reassortants with intermediate replication kinetics and pharmacological inhibitors of reovirus replication, IFN responses were found to inversely correlate with kinetics of virus replication. In other words, slow-replicating T3D strains induce more IFN signalling than fast-replicating T3D strains. Paradoxically, during co-infections by T3DPL and T3DTD, there was still high IRF3 phosphorylation indicating a phenodominant effect by the slow-replicating T3DTD. Using silencing and knock-out of RIG-I to impede IFN, we found that IFN induction does not affect the first round of reovirus replication but does prevent cell-cell spread in a paracrine fashion. Accordingly, during co-infections, T3DPL continues to replicate robustly despite activation of IFN by T3DTD. Using gene expression analysis, we discovered that reovirus can also induce a subset of genes in a RIG-I and IFN-independent manner; these genes were induced more by T3DPL than T3DTD. Polymorphisms in reovirus σ3 viral protein were found to control activation of RIG-I/ IFN-independent genes. Altogether, the study reveals that single amino acid polymorphisms in reovirus genomes can have large impact on host gene expression, by both changing replication kinetics and by modifying viral protein activity, such that two closely related T3D strains can induce opposite cytokine landscapes.
Identifiants
pubmed: 32956403
doi: 10.1371/journal.ppat.1008803
pii: PPATHOGENS-D-20-00031
pmc: PMC7529228
doi:
Substances chimiques
Capsid Proteins
0
Cytokines
0
IRF3 protein, human
0
Interferon Regulatory Factor-3
0
PLAAT4 protein, human
0
RNA, Double-Stranded
0
RNA, Viral
0
RNA-Binding Proteins
0
Receptors, Retinoic Acid
0
sigma protein 3, Reovirus
0
Interferons
9008-11-1
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008803Subventions
Organisme : CIHR
Pays : Canada
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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