Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis.
Identifieur interne : 001575 ( Main/Exploration ); précédent : 001574; suivant : 001576Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis.
Auteurs : Jose L. Nieto-Torres [Espagne] ; Marta L. Dediego [Espagne] ; Carmina Verdiá-Báguena [Espagne] ; Jose M. Jimenez-Guarde O [Espagne] ; Jose A. Regla-Nava [Espagne] ; Raul Fernandez-Delgado [Espagne] ; Carlos Casta O-Rodriguez [Espagne] ; Antonio Alcaraz [Espagne] ; Jaume Torres [Singapour] ; Vicente M. Aguilella [Espagne] ; Luis Enjuanes [Espagne]Source :
- PLoS pathogens [ 1553-7374 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Canaux ioniques (), Canaux ioniques (génétique), Canaux ioniques (physiologie), Cellules Vero, Cellules cultivées, Cricetinae, Femelle, Interactions hôte-pathogène (génétique), Modèles moléculaires, Organismes génétiquement modifiés, Protéines de l'enveloppe virale (), Protéines de l'enveloppe virale (génétique), Protéines de l'enveloppe virale (physiologie), Souris, Souris de lignée BALB C, Structure tertiaire des protéines, Syndrome respiratoire aigu sévère (virologie), Séquence d'acides aminés, Virus du SRAS (croissance et développement), Virus du SRAS (génétique), Virus du SRAS (pathogénicité).
- MESH :
- croissance et développement : Virus du SRAS.
- génétique : Canaux ioniques, Interactions hôte-pathogène, Protéines de l'enveloppe virale, Virus du SRAS.
- pathogénicité : Virus du SRAS.
- physiologie : Canaux ioniques, Protéines de l'enveloppe virale.
- virologie : Syndrome respiratoire aigu sévère.
- Animaux, Canaux ioniques, Cellules Vero, Cellules cultivées, Cricetinae, Femelle, Modèles moléculaires, Organismes génétiquement modifiés, Protéines de l'enveloppe virale, Souris, Souris de lignée BALB C, Structure tertiaire des protéines, Séquence d'acides aminés.
English descriptors
- KwdEn :
- Amino Acid Sequence, Animals, Cells, Cultured, Chlorocebus aethiops, Cricetinae, Female, Host-Pathogen Interactions (genetics), Ion Channels (chemistry), Ion Channels (genetics), Ion Channels (physiology), Mice, Mice, Inbred BALB C, Models, Molecular, Organisms, Genetically Modified, Protein Structure, Tertiary, SARS Virus (genetics), SARS Virus (growth & development), SARS Virus (pathogenicity), Severe Acute Respiratory Syndrome (virology), Vero Cells, Viral Envelope Proteins (chemistry), Viral Envelope Proteins (genetics), Viral Envelope Proteins (physiology).
- MESH :
- chemical , chemistry : Ion Channels, Viral Envelope Proteins.
- genetics : Host-Pathogen Interactions, Ion Channels, SARS Virus, Viral Envelope Proteins.
- growth & development : SARS Virus.
- pathogenicity : SARS Virus.
- chemical , physiology : Ion Channels, Viral Envelope Proteins.
- virology : Severe Acute Respiratory Syndrome.
- Amino Acid Sequence, Animals, Cells, Cultured, Chlorocebus aethiops, Cricetinae, Female, Mice, Mice, Inbred BALB C, Models, Molecular, Organisms, Genetically Modified, Protein Structure, Tertiary, Vero Cells.
Abstract
Deletion of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) envelope (E) gene attenuates the virus. E gene encodes a small multifunctional protein that possesses ion channel (IC) activity, an important function in virus-host interaction. To test the contribution of E protein IC activity in virus pathogenesis, two recombinant mouse-adapted SARS-CoVs, each containing one single amino acid mutation that suppressed ion conductivity, were engineered. After serial infections, mutant viruses, in general, incorporated compensatory mutations within E gene that rendered active ion channels. Furthermore, IC activity conferred better fitness in competition assays, suggesting that ion conductivity represents an advantage for the virus. Interestingly, mice infected with viruses displaying E protein IC activity, either with the wild-type E protein sequence or with the revertants that restored ion transport, rapidly lost weight and died. In contrast, mice infected with mutants lacking IC activity, which did not incorporate mutations within E gene during the experiment, recovered from disease and most survived. Knocking down E protein IC activity did not significantly affect virus growth in infected mice but decreased edema accumulation, the major determinant of acute respiratory distress syndrome (ARDS) leading to death. Reduced edema correlated with lung epithelia integrity and proper localization of Na+/K+ ATPase, which participates in edema resolution. Levels of inflammasome-activated IL-1β were reduced in the lung airways of the animals infected with viruses lacking E protein IC activity, indicating that E protein IC function is required for inflammasome activation. Reduction of IL-1β was accompanied by diminished amounts of TNF and IL-6 in the absence of E protein ion conductivity. All these key cytokines promote the progression of lung damage and ARDS pathology. In conclusion, E protein IC activity represents a new determinant for SARS-CoV virulence.
DOI: 10.1371/journal.ppat.1004077
PubMed: 24788150
Affiliations:
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Nieto-Torres</name><affiliation wicri:level="4"><nlm:affiliation>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName><orgName type="university">Université autonome de Madrid</orgName></affiliation></author><author><name sortKey="Dediego, Marta L" sort="Dediego, Marta L" uniqKey="Dediego M" first="Marta L" last="Dediego">Marta L. Dediego</name><affiliation wicri:level="4"><nlm:affiliation>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName><orgName type="university">Université autonome de Madrid</orgName></affiliation></author><author><name sortKey="Verdia Baguena, Carmina" sort="Verdia Baguena, Carmina" uniqKey="Verdia Baguena C" first="Carmina" last="Verdiá-Báguena">Carmina Verdiá-Báguena</name><affiliation wicri:level="1"><nlm:affiliation>Department of Physics, Laboratory of Molecular Biophysics. Universitat Jaume I, Castellón, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Physics, Laboratory of Molecular Biophysics. Universitat Jaume I, Castellón</wicri:regionArea><wicri:noRegion>Castellón</wicri:noRegion></affiliation></author><author><name sortKey="Jimenez Guarde O, Jose M" sort="Jimenez Guarde O, Jose M" uniqKey="Jimenez Guarde O J" first="Jose M" last="Jimenez-Guarde O">Jose M. Jimenez-Guarde O</name><affiliation wicri:level="4"><nlm:affiliation>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName><orgName type="university">Université autonome de Madrid</orgName></affiliation></author><author><name sortKey="Regla Nava, Jose A" sort="Regla Nava, Jose A" uniqKey="Regla Nava J" first="Jose A" last="Regla-Nava">Jose A. Regla-Nava</name><affiliation wicri:level="4"><nlm:affiliation>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName><orgName type="university">Université autonome de Madrid</orgName></affiliation></author><author><name sortKey="Fernandez Delgado, Raul" sort="Fernandez Delgado, Raul" uniqKey="Fernandez Delgado R" first="Raul" last="Fernandez-Delgado">Raul Fernandez-Delgado</name><affiliation wicri:level="4"><nlm:affiliation>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName><orgName type="university">Université autonome de Madrid</orgName></affiliation></author><author><name sortKey="Casta O Rodriguez, Carlos" sort="Casta O Rodriguez, Carlos" uniqKey="Casta O Rodriguez C" first="Carlos" last="Casta O-Rodriguez">Carlos Casta O-Rodriguez</name><affiliation wicri:level="4"><nlm:affiliation>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName><orgName type="university">Université autonome de Madrid</orgName></affiliation></author><author><name sortKey="Alcaraz, Antonio" sort="Alcaraz, Antonio" uniqKey="Alcaraz A" first="Antonio" last="Alcaraz">Antonio Alcaraz</name><affiliation wicri:level="1"><nlm:affiliation>Department of Physics, Laboratory of Molecular Biophysics. Universitat Jaume I, Castellón, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Physics, Laboratory of Molecular Biophysics. Universitat Jaume I, Castellón</wicri:regionArea><wicri:noRegion>Castellón</wicri:noRegion></affiliation></author><author><name sortKey="Torres, Jaume" sort="Torres, Jaume" uniqKey="Torres J" first="Jaume" last="Torres">Jaume Torres</name><affiliation wicri:level="1"><nlm:affiliation>School of Biological Sciences, Division of Structural and Computational Biology, Nanyang Technological University, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>School of Biological Sciences, Division of Structural and Computational Biology, Nanyang Technological University, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Aguilella, Vicente M" sort="Aguilella, Vicente M" uniqKey="Aguilella V" first="Vicente M" last="Aguilella">Vicente M. Aguilella</name><affiliation wicri:level="1"><nlm:affiliation>Department of Physics, Laboratory of Molecular Biophysics. Universitat Jaume I, Castellón, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Physics, Laboratory of Molecular Biophysics. Universitat Jaume I, Castellón</wicri:regionArea><wicri:noRegion>Castellón</wicri:noRegion></affiliation></author><author><name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name><affiliation wicri:level="4"><nlm:affiliation>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName><orgName type="university">Université autonome de Madrid</orgName></affiliation></author></analytic><series><title level="j">PLoS pathogens</title><idno type="eISSN">1553-7374</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Cells, Cultured</term><term>Chlorocebus aethiops</term><term>Cricetinae</term><term>Female</term><term>Host-Pathogen Interactions (genetics)</term><term>Ion Channels (chemistry)</term><term>Ion Channels (genetics)</term><term>Ion Channels (physiology)</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Models, Molecular</term><term>Organisms, Genetically Modified</term><term>Protein Structure, Tertiary</term><term>SARS Virus (genetics)</term><term>SARS Virus (growth & development)</term><term>SARS Virus (pathogenicity)</term><term>Severe Acute Respiratory Syndrome (virology)</term><term>Vero Cells</term><term>Viral Envelope Proteins (chemistry)</term><term>Viral Envelope Proteins (genetics)</term><term>Viral Envelope Proteins (physiology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Canaux ioniques ()</term><term>Canaux ioniques (génétique)</term><term>Canaux ioniques (physiologie)</term><term>Cellules Vero</term><term>Cellules cultivées</term><term>Cricetinae</term><term>Femelle</term><term>Interactions hôte-pathogène (génétique)</term><term>Modèles moléculaires</term><term>Organismes génétiquement modifiés</term><term>Protéines de l'enveloppe virale ()</term><term>Protéines de l'enveloppe virale (génétique)</term><term>Protéines de l'enveloppe virale (physiologie)</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Structure tertiaire des protéines</term><term>Syndrome respiratoire aigu sévère (virologie)</term><term>Séquence d'acides aminés</term><term>Virus du SRAS (croissance et développement)</term><term>Virus du SRAS (génétique)</term><term>Virus du SRAS (pathogénicité)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Ion Channels</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" qualifier="croissance et développement" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Host-Pathogen Interactions</term><term>Ion Channels</term><term>SARS Virus</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" qualifier="growth & development" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Canaux ioniques</term><term>Interactions hôte-pathogène</term><term>Protéines de l'enveloppe virale</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Canaux ioniques</term><term>Protéines de l'enveloppe virale</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Ion Channels</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Cells, Cultured</term><term>Chlorocebus aethiops</term><term>Cricetinae</term><term>Female</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Models, Molecular</term><term>Organisms, Genetically Modified</term><term>Protein Structure, Tertiary</term><term>Vero Cells</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Canaux ioniques</term><term>Cellules Vero</term><term>Cellules cultivées</term><term>Cricetinae</term><term>Femelle</term><term>Modèles moléculaires</term><term>Organismes génétiquement modifiés</term><term>Protéines de l'enveloppe virale</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Structure tertiaire des protéines</term><term>Séquence d'acides aminés</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Deletion of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) envelope (E) gene attenuates the virus. E gene encodes a small multifunctional protein that possesses ion channel (IC) activity, an important function in virus-host interaction. To test the contribution of E protein IC activity in virus pathogenesis, two recombinant mouse-adapted SARS-CoVs, each containing one single amino acid mutation that suppressed ion conductivity, were engineered. After serial infections, mutant viruses, in general, incorporated compensatory mutations within E gene that rendered active ion channels. Furthermore, IC activity conferred better fitness in competition assays, suggesting that ion conductivity represents an advantage for the virus. Interestingly, mice infected with viruses displaying E protein IC activity, either with the wild-type E protein sequence or with the revertants that restored ion transport, rapidly lost weight and died. In contrast, mice infected with mutants lacking IC activity, which did not incorporate mutations within E gene during the experiment, recovered from disease and most survived. Knocking down E protein IC activity did not significantly affect virus growth in infected mice but decreased edema accumulation, the major determinant of acute respiratory distress syndrome (ARDS) leading to death. Reduced edema correlated with lung epithelia integrity and proper localization of Na+/K+ ATPase, which participates in edema resolution. Levels of inflammasome-activated IL-1β were reduced in the lung airways of the animals infected with viruses lacking E protein IC activity, indicating that E protein IC function is required for inflammasome activation. Reduction of IL-1β was accompanied by diminished amounts of TNF and IL-6 in the absence of E protein ion conductivity. All these key cytokines promote the progression of lung damage and ARDS pathology. In conclusion, E protein IC activity represents a new determinant for SARS-CoV virulence. </div></front></TEI><affiliations><list><country><li>Espagne</li><li>Singapour</li></country><region><li>Communauté de Madrid</li></region><settlement><li>Madrid</li></settlement><orgName><li>Université autonome de Madrid</li></orgName></list><tree><country name="Espagne"><region name="Communauté de Madrid"><name sortKey="Nieto Torres, Jose L" sort="Nieto Torres, Jose L" uniqKey="Nieto Torres J" first="Jose L" last="Nieto-Torres">Jose L. Nieto-Torres</name></region><name sortKey="Aguilella, Vicente M" sort="Aguilella, Vicente M" uniqKey="Aguilella V" first="Vicente M" last="Aguilella">Vicente M. Aguilella</name><name sortKey="Alcaraz, Antonio" sort="Alcaraz, Antonio" uniqKey="Alcaraz A" first="Antonio" last="Alcaraz">Antonio Alcaraz</name><name sortKey="Casta O Rodriguez, Carlos" sort="Casta O Rodriguez, Carlos" uniqKey="Casta O Rodriguez C" first="Carlos" last="Casta O-Rodriguez">Carlos Casta O-Rodriguez</name><name sortKey="Dediego, Marta L" sort="Dediego, Marta L" uniqKey="Dediego M" first="Marta L" last="Dediego">Marta L. Dediego</name><name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name><name sortKey="Fernandez Delgado, Raul" sort="Fernandez Delgado, Raul" uniqKey="Fernandez Delgado R" first="Raul" last="Fernandez-Delgado">Raul Fernandez-Delgado</name><name sortKey="Jimenez Guarde O, Jose M" sort="Jimenez Guarde O, Jose M" uniqKey="Jimenez Guarde O J" first="Jose M" last="Jimenez-Guarde O">Jose M. Jimenez-Guarde O</name><name sortKey="Regla Nava, Jose A" sort="Regla Nava, Jose A" uniqKey="Regla Nava J" first="Jose A" last="Regla-Nava">Jose A. Regla-Nava</name><name sortKey="Verdia Baguena, Carmina" sort="Verdia Baguena, Carmina" uniqKey="Verdia Baguena C" first="Carmina" last="Verdiá-Báguena">Carmina Verdiá-Báguena</name></country><country name="Singapour"><noRegion><name sortKey="Torres, Jaume" sort="Torres, Jaume" uniqKey="Torres J" first="Jaume" last="Torres">Jaume Torres</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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