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...
Gespeichert in:
Veröffentlicht in: | PLoS pathogens 2023-09, Vol.19 (9), p.e1011446-e1011446 |
---|---|
Hauptverfasser: | , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | e1011446 |
---|---|
container_issue | 9 |
container_start_page | e1011446 |
container_title | PLoS pathogens |
container_volume | 19 |
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 |
format | Article |
fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_3069180221</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A767592850</galeid><doaj_id>oai_doaj_org_article_4f14a3acc343497b9372e77d19cad9d9</doaj_id><sourcerecordid>A767592850</sourcerecordid><originalsourceid>FETCH-LOGICAL-c626t-12d65c23f2a6a4dc60bd1f991a46d1deda38cd8186a5cf524273207a0c349ce93</originalsourceid><addsrcrecordid>eNqVk82O0zAQxyMEYpeFN0DCEhc4tPgrcXJCVQVspQokFi5crInttC5p3LWdiD4E74xDA6KrvSAfbI1_85_xjCfLnhM8J0yQNzvX-w7a-eEAcU4wIZwXD7JLkudsJpjgD_85X2RPQthhzAkjxePsggnBWInFZfbzpg_KHKKtbWvjEUWHvtnvgAbr-4BshwAtXdtC7TxEOxi09C4EtHd9MChEDwmxI6h7ZTSqj2jlG4a0aayyplPHUWOw0TtU9xF5c9tbbwJycWs8GsBb6GI4QYN7mj1qoA3m2bRfZV_fv_uyvJ6tP31YLRfrmSpoEWeE6iJXlDUUCuBaFbjWpKkqArzQRBsNrFS6JGUBuWpyyqlgFAvAivFKmYpdZS9OuofWBTlVMkiGi4qUmFKSiNWJ0A528uDtHvxROrDyt8H5jQQfrWqN5A3hwEAl8SQv6ooJaoTQpFKgKz1GeztF6-u90cp0qW7tmej5TWe3cuMGSXDORUo8KcxOCts7fteLtTxAiKb3EnOGWZ6TYcz-1RTRu9vehCj3NrU59bEzqXOSlkVJaE4FTejLO-j95ZioDaQX265xKVE1isqFKERe0TLHiZrfQ6Wlzd4q16VPkexnDq_PHBITzY-4gT4Eubr5_B_sx3OWn1g1_lZvmr9FI1iO0_PnkXKcHjlND_sFOZYM0w</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3069180221</pqid></control><display><type>article</type><title>Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced by Irf3 deficiency in vitro but requires other variants in vivo</title><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>PubMed Central Open Access</source><source>Public Library of Science (PLoS)</source><creator>Bourdon, Marie ; Manet, Caroline ; Conquet, Laurine ; Ramaugé Parra, Corentin ; Kornobis, Etienne ; Bonnefoy, Eliette ; Montagutelli, Xavier</creator><contributor>St. John, Ashley L.</contributor><creatorcontrib>Bourdon, Marie ; Manet, Caroline ; Conquet, Laurine ; Ramaugé Parra, Corentin ; Kornobis, Etienne ; Bonnefoy, Eliette ; Montagutelli, Xavier ; St. John, Ashley L.</creatorcontrib><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.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1011446</identifier><identifier>PMID: 37733807</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>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</subject><ispartof>PLoS pathogens, 2023-09, Vol.19 (9), p.e1011446-e1011446</ispartof><rights>COPYRIGHT 2023 Public Library of Science</rights><rights>2023 Bourdon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Attribution</rights><rights>2023 Bourdon et al 2023 Bourdon et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c626t-12d65c23f2a6a4dc60bd1f991a46d1deda38cd8186a5cf524273207a0c349ce93</cites><orcidid>0000-0002-9372-5398 ; 0000-0002-6184-1888 ; 0000-0001-7712-8270 ; 0000-0002-9534-2104</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547207/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547207/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://pasteur.hal.science/pasteur-04303551$$DView record in HAL$$Hfree_for_read</backlink></links><search><contributor>St. John, Ashley L.</contributor><creatorcontrib>Bourdon, Marie</creatorcontrib><creatorcontrib>Manet, Caroline</creatorcontrib><creatorcontrib>Conquet, Laurine</creatorcontrib><creatorcontrib>Ramaugé Parra, Corentin</creatorcontrib><creatorcontrib>Kornobis, Etienne</creatorcontrib><creatorcontrib>Bonnefoy, Eliette</creatorcontrib><creatorcontrib>Montagutelli, Xavier</creatorcontrib><title>Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced by Irf3 deficiency in vitro but requires other variants in vivo</title><title>PLoS pathogens</title><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.</description><subject>Alleles</subject><subject>Analysis</subject><subject>Asymptomatic infection</subject><subject>Biological response modifiers</subject><subject>Biology and Life Sciences</subject><subject>Coccidioidomycosis</subject><subject>Collaboration</subject><subject>Dengue fever</subject><subject>Dengue viruses</subject><subject>Disease</subject><subject>Embryo fibroblasts</subject><subject>Epidemics</subject><subject>Fetuses</subject><subject>Flaviviridae</subject><subject>Genes</subject><subject>Genetic analysis</subject><subject>Genetic diversity</subject><subject>Genetic variance</subject><subject>Guillain-Barre syndrome</subject><subject>Health aspects</subject><subject>Inbreeding</subject><subject>Infections</subject><subject>Interferon</subject><subject>Interferon regulatory factor 3</subject><subject>Lethality</subject><subject>Life Sciences</subject><subject>Medicine and Health Sciences</subject><subject>Mutation</subject><subject>Neurological diseases</subject><subject>Phosphorylation</subject><subject>Physical Sciences</subject><subject>Replication</subject><subject>Research and analysis methods</subject><subject>Rift Valley fever</subject><subject>Sensors</subject><subject>Signs and symptoms</subject><subject>Strains (organisms)</subject><subject>Vector-borne diseases</subject><subject>Viral diseases</subject><subject>Viruses</subject><subject>West Nile fever</subject><subject>West Nile virus</subject><subject>Zika virus</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqVk82O0zAQxyMEYpeFN0DCEhc4tPgrcXJCVQVspQokFi5crInttC5p3LWdiD4E74xDA6KrvSAfbI1_85_xjCfLnhM8J0yQNzvX-w7a-eEAcU4wIZwXD7JLkudsJpjgD_85X2RPQthhzAkjxePsggnBWInFZfbzpg_KHKKtbWvjEUWHvtnvgAbr-4BshwAtXdtC7TxEOxi09C4EtHd9MChEDwmxI6h7ZTSqj2jlG4a0aayyplPHUWOw0TtU9xF5c9tbbwJycWs8GsBb6GI4QYN7mj1qoA3m2bRfZV_fv_uyvJ6tP31YLRfrmSpoEWeE6iJXlDUUCuBaFbjWpKkqArzQRBsNrFS6JGUBuWpyyqlgFAvAivFKmYpdZS9OuofWBTlVMkiGi4qUmFKSiNWJ0A528uDtHvxROrDyt8H5jQQfrWqN5A3hwEAl8SQv6ooJaoTQpFKgKz1GeztF6-u90cp0qW7tmej5TWe3cuMGSXDORUo8KcxOCts7fteLtTxAiKb3EnOGWZ6TYcz-1RTRu9vehCj3NrU59bEzqXOSlkVJaE4FTejLO-j95ZioDaQX265xKVE1isqFKERe0TLHiZrfQ6Wlzd4q16VPkexnDq_PHBITzY-4gT4Eubr5_B_sx3OWn1g1_lZvmr9FI1iO0_PnkXKcHjlND_sFOZYM0w</recordid><startdate>20230921</startdate><enddate>20230921</enddate><creator>Bourdon, Marie</creator><creator>Manet, Caroline</creator><creator>Conquet, Laurine</creator><creator>Ramaugé Parra, Corentin</creator><creator>Kornobis, Etienne</creator><creator>Bonnefoy, Eliette</creator><creator>Montagutelli, Xavier</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>AAYXX</scope><scope>CITATION</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>COVID</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-9372-5398</orcidid><orcidid>https://orcid.org/0000-0002-6184-1888</orcidid><orcidid>https://orcid.org/0000-0001-7712-8270</orcidid><orcidid>https://orcid.org/0000-0002-9534-2104</orcidid></search><sort><creationdate>20230921</creationdate><title>Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced by Irf3 deficiency in vitro but requires other variants in vivo</title><author>Bourdon, Marie ; Manet, Caroline ; Conquet, Laurine ; Ramaugé Parra, Corentin ; Kornobis, Etienne ; Bonnefoy, Eliette ; Montagutelli, Xavier</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c626t-12d65c23f2a6a4dc60bd1f991a46d1deda38cd8186a5cf524273207a0c349ce93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Alleles</topic><topic>Analysis</topic><topic>Asymptomatic infection</topic><topic>Biological response modifiers</topic><topic>Biology and Life Sciences</topic><topic>Coccidioidomycosis</topic><topic>Collaboration</topic><topic>Dengue fever</topic><topic>Dengue viruses</topic><topic>Disease</topic><topic>Embryo fibroblasts</topic><topic>Epidemics</topic><topic>Fetuses</topic><topic>Flaviviridae</topic><topic>Genes</topic><topic>Genetic analysis</topic><topic>Genetic diversity</topic><topic>Genetic variance</topic><topic>Guillain-Barre syndrome</topic><topic>Health aspects</topic><topic>Inbreeding</topic><topic>Infections</topic><topic>Interferon</topic><topic>Interferon regulatory factor 3</topic><topic>Lethality</topic><topic>Life Sciences</topic><topic>Medicine and Health Sciences</topic><topic>Mutation</topic><topic>Neurological diseases</topic><topic>Phosphorylation</topic><topic>Physical Sciences</topic><topic>Replication</topic><topic>Research and analysis methods</topic><topic>Rift Valley fever</topic><topic>Sensors</topic><topic>Signs and symptoms</topic><topic>Strains (organisms)</topic><topic>Vector-borne diseases</topic><topic>Viral diseases</topic><topic>Viruses</topic><topic>West Nile fever</topic><topic>West Nile virus</topic><topic>Zika virus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bourdon, Marie</creatorcontrib><creatorcontrib>Manet, Caroline</creatorcontrib><creatorcontrib>Conquet, Laurine</creatorcontrib><creatorcontrib>Ramaugé Parra, Corentin</creatorcontrib><creatorcontrib>Kornobis, Etienne</creatorcontrib><creatorcontrib>Bonnefoy, Eliette</creatorcontrib><creatorcontrib>Montagutelli, Xavier</creatorcontrib><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>Coronavirus Research Database</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bourdon, Marie</au><au>Manet, Caroline</au><au>Conquet, Laurine</au><au>Ramaugé Parra, Corentin</au><au>Kornobis, Etienne</au><au>Bonnefoy, Eliette</au><au>Montagutelli, Xavier</au><au>St. John, Ashley L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced by Irf3 deficiency in vitro but requires other variants in vivo</atitle><jtitle>PLoS pathogens</jtitle><date>2023-09-21</date><risdate>2023</risdate><volume>19</volume><issue>9</issue><spage>e1011446</spage><epage>e1011446</epage><pages>e1011446-e1011446</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>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.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>37733807</pmid><doi>10.1371/journal.ppat.1011446</doi><tpages>e1011446</tpages><orcidid>https://orcid.org/0000-0002-9372-5398</orcidid><orcidid>https://orcid.org/0000-0002-6184-1888</orcidid><orcidid>https://orcid.org/0000-0001-7712-8270</orcidid><orcidid>https://orcid.org/0000-0002-9534-2104</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1553-7374 |
ispartof | PLoS pathogens, 2023-09, Vol.19 (9), p.e1011446-e1011446 |
issn | 1553-7374 1553-7366 1553-7374 |
language | eng |
recordid | cdi_plos_journals_3069180221 |
source | DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access; Public Library of Science (PLoS) |
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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T11%3A44%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Susceptibility%20to%20Zika%20virus%20in%20a%20Collaborative%20Cross%20mouse%20strain%20is%20induced%20by%20Irf3%20deficiency%20in%20vitro%20but%20requires%20other%20variants%20in%20vivo&rft.jtitle=PLoS%20pathogens&rft.au=Bourdon,%20Marie&rft.date=2023-09-21&rft.volume=19&rft.issue=9&rft.spage=e1011446&rft.epage=e1011446&rft.pages=e1011446-e1011446&rft.issn=1553-7374&rft.eissn=1553-7374&rft_id=info:doi/10.1371/journal.ppat.1011446&rft_dat=%3Cgale_plos_%3EA767592850%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3069180221&rft_id=info:pmid/37733807&rft_galeid=A767592850&rft_doaj_id=oai_doaj_org_article_4f14a3acc343497b9372e77d19cad9d9&rfr_iscdi=true |