Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced by Irf3 deficiency in vitro but requires other variants in vivo

Zika virus (ZIKV) is a Flavivirus responsible for recent epidemics in Pacific Islands and in the Americas. In humans, the consequences of ZIKV infection range from asymptomatic infection to severe neurological disease such as Guillain-Barré syndrome or fetal neurodevelopmental defects, suggesting, a...

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Veröffentlicht in:PLoS pathogens 2023-09, Vol.19 (9), p.e1011446-e1011446
Hauptverfasser: Bourdon, Marie, Manet, Caroline, Conquet, Laurine, Ramaugé Parra, Corentin, Kornobis, Etienne, Bonnefoy, Eliette, Montagutelli, Xavier
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container_issue 9
container_start_page e1011446
container_title PLoS pathogens
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creator Bourdon, Marie
Manet, Caroline
Conquet, Laurine
Ramaugé Parra, Corentin
Kornobis, Etienne
Bonnefoy, Eliette
Montagutelli, Xavier
description Zika virus (ZIKV) is a Flavivirus responsible for recent epidemics in Pacific Islands and in the Americas. In humans, the consequences of ZIKV infection range from asymptomatic infection to severe neurological disease such as Guillain-Barré syndrome or fetal neurodevelopmental defects, suggesting, among other factors, the influence of host genetic variants. We previously reported similar diverse outcomes of ZIKV infection in mice of the Collaborative Cross (CC), a collection of inbred strains with large genetic diversity. CC071/TauUnc (CC071) was the most susceptible CC strain with severe symptoms and lethality. Notably, CC071 has been recently reported to be also susceptible to other flaviviruses including dengue virus, Powassan virus, West Nile virus, and to Rift Valley fever virus. To identify the genetic origin of this broad susceptibility, we investigated ZIKV replication in mouse embryonic fibroblasts (MEFs) from CC071 and two resistant strains. CC071 showed uncontrolled ZIKV replication associated with delayed induction of type-I interferons (IFN-I). Genetic analysis identified a mutation in the Irf3 gene specific to the CC071 strain which prevents the protein phosphorylation required to activate interferon beta transcription. We demonstrated that this mutation induces the same defective IFN-I response and uncontrolled viral replication in MEFs as an Irf3 knock-out allele. By contrast, we also showed that Irf3 deficiency did not induce the high plasma viral load and clinical severity observed in CC071 mice and that susceptibility alleles at other genes, not associated with the IFN-I response, are required. Our results provide new insight into the in vitro and in vivo roles of Irf3, and into the genetic complexity of host responses to flaviviruses.
doi_str_mv 10.1371/journal.ppat.1011446
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In humans, the consequences of ZIKV infection range from asymptomatic infection to severe neurological disease such as Guillain-Barré syndrome or fetal neurodevelopmental defects, suggesting, among other factors, the influence of host genetic variants. We previously reported similar diverse outcomes of ZIKV infection in mice of the Collaborative Cross (CC), a collection of inbred strains with large genetic diversity. CC071/TauUnc (CC071) was the most susceptible CC strain with severe symptoms and lethality. Notably, CC071 has been recently reported to be also susceptible to other flaviviruses including dengue virus, Powassan virus, West Nile virus, and to Rift Valley fever virus. To identify the genetic origin of this broad susceptibility, we investigated ZIKV replication in mouse embryonic fibroblasts (MEFs) from CC071 and two resistant strains. CC071 showed uncontrolled ZIKV replication associated with delayed induction of type-I interferons (IFN-I). Genetic analysis identified a mutation in the Irf3 gene specific to the CC071 strain which prevents the protein phosphorylation required to activate interferon beta transcription. We demonstrated that this mutation induces the same defective IFN-I response and uncontrolled viral replication in MEFs as an Irf3 knock-out allele. By contrast, we also showed that Irf3 deficiency did not induce the high plasma viral load and clinical severity observed in CC071 mice and that susceptibility alleles at other genes, not associated with the IFN-I response, are required. 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Genetic analysis identified a mutation in the Irf3 gene specific to the CC071 strain which prevents the protein phosphorylation required to activate interferon beta transcription. We demonstrated that this mutation induces the same defective IFN-I response and uncontrolled viral replication in MEFs as an Irf3 knock-out allele. By contrast, we also showed that Irf3 deficiency did not induce the high plasma viral load and clinical severity observed in CC071 mice and that susceptibility alleles at other genes, not associated with the IFN-I response, are required. 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subjects Alleles
Analysis
Asymptomatic infection
Biological response modifiers
Biology and Life Sciences
Coccidioidomycosis
Collaboration
Dengue fever
Dengue viruses
Disease
Embryo fibroblasts
Epidemics
Fetuses
Flaviviridae
Genes
Genetic analysis
Genetic diversity
Genetic variance
Guillain-Barre syndrome
Health aspects
Inbreeding
Infections
Interferon
Interferon regulatory factor 3
Lethality
Life Sciences
Medicine and Health Sciences
Mutation
Neurological diseases
Phosphorylation
Physical Sciences
Replication
Research and analysis methods
Rift Valley fever
Sensors
Signs and symptoms
Strains (organisms)
Vector-borne diseases
Viral diseases
Viruses
West Nile fever
West Nile virus
Zika virus
title Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced by Irf3 deficiency in vitro but requires other variants in vivo
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