Stress Granule-Inducing Eukaryotic Translation Initiation Factor 4A Inhibitors Block Influenza A Virus Replication.
Identifieur interne : 000A64 ( Main/Exploration ); précédent : 000A63; suivant : 000A65Stress Granule-Inducing Eukaryotic Translation Initiation Factor 4A Inhibitors Block Influenza A Virus Replication.
Auteurs : Patrick D. Slaine [Canada] ; Mariel Kleer [Canada] ; Nathan K. Smith [Canada] ; Denys A. Khaperskyy [Canada] ; Craig Mccormick [Canada]Source :
- Viruses [ 1999-4915 ] ; 2017.
Descripteurs français
- KwdFr :
- Antienzymes (métabolisme), Antiviraux (métabolisme), Biosynthèse des protéines (), Cellules A549, Composés époxy (métabolisme), Facteur-4A d'initiation eucaryote (antagonistes et inhibiteurs), Humains, Macrolides (métabolisme), Réplication virale (), Thiazoles (métabolisme), Triterpènes (métabolisme), Virus de la grippe A (physiologie).
- MESH :
- antagonistes et inhibiteurs : Facteur-4A d'initiation eucaryote.
- métabolisme : Antienzymes, Antiviraux, Composés époxy, Macrolides, Thiazoles, Triterpènes.
- physiologie : Virus de la grippe A.
- Biosynthèse des protéines, Cellules A549, Humains, Réplication virale.
English descriptors
- KwdEn :
- A549 Cells, Antiviral Agents (metabolism), Enzyme Inhibitors (metabolism), Epoxy Compounds (metabolism), Eukaryotic Initiation Factor-4A (antagonists & inhibitors), Humans, Influenza A virus (physiology), Macrolides (metabolism), Protein Biosynthesis (drug effects), Thiazoles (metabolism), Triterpenes (metabolism), Virus Replication (drug effects).
- MESH :
- chemical , antagonists & inhibitors : Eukaryotic Initiation Factor-4A.
- chemical , metabolism : Antiviral Agents, Enzyme Inhibitors, Epoxy Compounds, Macrolides, Thiazoles, Triterpenes.
- drug effects : Protein Biosynthesis, Virus Replication.
- physiology : Influenza A virus.
- A549 Cells, Humans.
Abstract
Eukaryotic translation initiation factor 4A (eIF4A) is a helicase that facilitates assembly of the translation preinitiation complex by unwinding structured mRNA 5' untranslated regions. Pateamine A (PatA) and silvestrol are natural products that disrupt eIF4A function and arrest translation, thereby triggering the formation of cytoplasmic aggregates of stalled preinitiation complexes known as stress granules (SGs). Here we examined the effects of eIF4A inhibition by PatA and silvestrol on influenza A virus (IAV) protein synthesis and replication in cell culture. Treatment of infected cells with either PatA or silvestrol at early times post-infection resulted in SG formation, arrest of viral protein synthesis and failure to replicate the viral genome. PatA, which irreversibly binds to eIF4A, sustained long-term blockade of IAV replication following drug withdrawal, and inhibited IAV replication at concentrations that had minimal cytotoxicity. By contrast, the antiviral effects of silvestrol were fully reversible; drug withdrawal caused rapid SG dissolution and resumption of viral protein synthesis. IAV inhibition by silvestrol was invariably associated with cytotoxicity. PatA blocked replication of genetically divergent IAV strains, suggesting common dependence on host eIF4A activity. This study demonstrates that the core host protein synthesis machinery can be targeted to block viral replication.
DOI: 10.3390/v9120388
PubMed: 29258238
Affiliations:
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Slaine</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada. patrick.slaine@dal.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2</wicri:regionArea><wicri:noRegion>NS B3H 4R2</wicri:noRegion></affiliation></author><author><name sortKey="Kleer, Mariel" sort="Kleer, Mariel" uniqKey="Kleer M" first="Mariel" last="Kleer">Mariel Kleer</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada. mariel.kleer@dal.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2</wicri:regionArea><wicri:noRegion>NS B3H 4R2</wicri:noRegion></affiliation></author><author><name sortKey="Smith, Nathan K" sort="Smith, Nathan K" uniqKey="Smith N" first="Nathan K" last="Smith">Nathan K. 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Slaine</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada. patrick.slaine@dal.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2</wicri:regionArea><wicri:noRegion>NS B3H 4R2</wicri:noRegion></affiliation></author><author><name sortKey="Kleer, Mariel" sort="Kleer, Mariel" uniqKey="Kleer M" first="Mariel" last="Kleer">Mariel Kleer</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada. mariel.kleer@dal.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2</wicri:regionArea><wicri:noRegion>NS B3H 4R2</wicri:noRegion></affiliation></author><author><name sortKey="Smith, Nathan K" sort="Smith, Nathan K" uniqKey="Smith N" first="Nathan K" last="Smith">Nathan K. Smith</name><affiliation wicri:level="1"><nlm:affiliation>Department of Community Health and Epidemiology, Dalhousie University, 5790 University Avenue, Halifax, NS B3H 1V7, Canada. nathansmith@dal.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Community Health and Epidemiology, Dalhousie University, 5790 University Avenue, Halifax, NS B3H 1V7</wicri:regionArea><wicri:noRegion>NS B3H 1V7</wicri:noRegion></affiliation></author><author><name sortKey="Khaperskyy, Denys A" sort="Khaperskyy, Denys A" uniqKey="Khaperskyy D" first="Denys A" last="Khaperskyy">Denys A. Khaperskyy</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada. d.khaperskyy@dal.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2</wicri:regionArea><wicri:noRegion>NS B3H 4R2</wicri:noRegion></affiliation></author><author><name sortKey="Mccormick, Craig" sort="Mccormick, Craig" uniqKey="Mccormick C" first="Craig" last="Mccormick">Craig Mccormick</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada. craig.mccormick@dal.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2</wicri:regionArea><wicri:noRegion>NS B3H 4R2</wicri:noRegion></affiliation></author></analytic><series><title level="j">Viruses</title><idno type="eISSN">1999-4915</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>A549 Cells</term><term>Antiviral Agents (metabolism)</term><term>Enzyme Inhibitors (metabolism)</term><term>Epoxy Compounds (metabolism)</term><term>Eukaryotic Initiation Factor-4A (antagonists & inhibitors)</term><term>Humans</term><term>Influenza A virus (physiology)</term><term>Macrolides (metabolism)</term><term>Protein Biosynthesis (drug effects)</term><term>Thiazoles (metabolism)</term><term>Triterpenes (metabolism)</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Antienzymes (métabolisme)</term><term>Antiviraux (métabolisme)</term><term>Biosynthèse des protéines ()</term><term>Cellules A549</term><term>Composés époxy (métabolisme)</term><term>Facteur-4A d'initiation eucaryote (antagonistes et inhibiteurs)</term><term>Humains</term><term>Macrolides (métabolisme)</term><term>Réplication virale ()</term><term>Thiazoles (métabolisme)</term><term>Triterpènes (métabolisme)</term><term>Virus de la grippe A (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Eukaryotic Initiation Factor-4A</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antiviral Agents</term><term>Enzyme Inhibitors</term><term>Epoxy Compounds</term><term>Macrolides</term><term>Thiazoles</term><term>Triterpenes</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Facteur-4A d'initiation eucaryote</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Protein Biosynthesis</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Antienzymes</term><term>Antiviraux</term><term>Composés époxy</term><term>Macrolides</term><term>Thiazoles</term><term>Triterpènes</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus de la grippe A</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Influenza A virus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>A549 Cells</term><term>Humans</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Biosynthèse des protéines</term><term>Cellules A549</term><term>Humains</term><term>Réplication virale</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Eukaryotic translation initiation factor 4A (eIF4A) is a helicase that facilitates assembly of the translation preinitiation complex by unwinding structured mRNA 5' untranslated regions. Pateamine A (PatA) and silvestrol are natural products that disrupt eIF4A function and arrest translation, thereby triggering the formation of cytoplasmic aggregates of stalled preinitiation complexes known as stress granules (SGs). Here we examined the effects of eIF4A inhibition by PatA and silvestrol on influenza A virus (IAV) protein synthesis and replication in cell culture. Treatment of infected cells with either PatA or silvestrol at early times post-infection resulted in SG formation, arrest of viral protein synthesis and failure to replicate the viral genome. PatA, which irreversibly binds to eIF4A, sustained long-term blockade of IAV replication following drug withdrawal, and inhibited IAV replication at concentrations that had minimal cytotoxicity. By contrast, the antiviral effects of silvestrol were fully reversible; drug withdrawal caused rapid SG dissolution and resumption of viral protein synthesis. IAV inhibition by silvestrol was invariably associated with cytotoxicity. PatA blocked replication of genetically divergent IAV strains, suggesting common dependence on host eIF4A activity. This study demonstrates that the core host protein synthesis machinery can be targeted to block viral replication.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Slaine, Patrick D" sort="Slaine, Patrick D" uniqKey="Slaine P" first="Patrick D" last="Slaine">Patrick D. Slaine</name></noRegion><name sortKey="Khaperskyy, Denys A" sort="Khaperskyy, Denys A" uniqKey="Khaperskyy D" first="Denys A" last="Khaperskyy">Denys A. Khaperskyy</name><name sortKey="Kleer, Mariel" sort="Kleer, Mariel" uniqKey="Kleer M" first="Mariel" last="Kleer">Mariel Kleer</name><name sortKey="Mccormick, Craig" sort="Mccormick, Craig" uniqKey="Mccormick C" first="Craig" last="Mccormick">Craig Mccormick</name><name sortKey="Smith, Nathan K" sort="Smith, Nathan K" uniqKey="Smith N" first="Nathan K" last="Smith">Nathan K. Smith</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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