PI3K-Akt-mTOR axis sustains rotavirus infection via the 4E-BP1 mediated autophagy pathway and represents an antiviral target.
Identifieur interne : 000529 ( Main/Exploration ); précédent : 000528; suivant : 000530PI3K-Akt-mTOR axis sustains rotavirus infection via the 4E-BP1 mediated autophagy pathway and represents an antiviral target.
Auteurs : Yuebang Yin [Pays-Bas] ; Wen Dang [Pays-Bas] ; Xinying Zhou [Pays-Bas] ; Lei Xu [Pays-Bas] ; Wenshi Wang [Pays-Bas] ; Wanlu Cao [Pays-Bas] ; Sunrui Chen [Pays-Bas] ; Junhong Su [République populaire de Chine] ; Xuepeng Cai [République populaire de Chine] ; Shaobo Xiao [République populaire de Chine] ; Maikel P. Peppelenbosch [Pays-Bas] ; Qiuwei Pan [Pays-Bas]Source :
- Virulence [ 2150-5608 ] ; 2018.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Antiviraux (pharmacologie), Autophagie (effets des médicaments et des substances chimiques), Cellules Caco-2 (MeSH), Cellules cultivées (MeSH), Humains (MeSH), Infections à rotavirus (anatomopathologie), Infections à rotavirus (métabolisme), Infections à rotavirus (virologie), Modèles biologiques (MeSH), Organoïdes (anatomopathologie), Organoïdes (métabolisme), Organoïdes (virologie), Phosphatidylinositol 3-kinases (métabolisme), Phosphoprotéines (antagonistes et inhibiteurs), Phosphoprotéines (génétique), Phosphoprotéines (métabolisme), Phosphorylation (effets des médicaments et des substances chimiques), Protéines adaptatrices de la transduction du signal (antagonistes et inhibiteurs), Protéines adaptatrices de la transduction du signal (génétique), Protéines adaptatrices de la transduction du signal (métabolisme), Protéines proto-oncogènes c-akt (métabolisme), Rotavirus (physiologie), Réplication virale (effets des médicaments et des substances chimiques), Souris (MeSH), Sérine-thréonine kinases TOR (antagonistes et inhibiteurs), Sérine-thréonine kinases TOR (génétique), Sérine-thréonine kinases TOR (métabolisme), Techniques de knock-down de gènes (MeSH), Transduction du signal (effets des médicaments et des substances chimiques).
- MESH :
- anatomopathologie : Infections à rotavirus, Organoïdes.
- antagonistes et inhibiteurs : Phosphoprotéines, Protéines adaptatrices de la transduction du signal, Sérine-thréonine kinases TOR.
- effets des médicaments et des substances chimiques : Autophagie, Phosphorylation, Réplication virale, Transduction du signal.
- génétique : Phosphoprotéines, Protéines adaptatrices de la transduction du signal, Sérine-thréonine kinases TOR.
- métabolisme : Infections à rotavirus, Organoïdes, Phosphatidylinositol 3-kinases, Phosphoprotéines, Protéines adaptatrices de la transduction du signal, Protéines proto-oncogènes c-akt, Sérine-thréonine kinases TOR.
- pharmacologie : Antiviraux.
- physiologie : Rotavirus.
- virologie : Infections à rotavirus, Organoïdes.
- Animaux, Cellules Caco-2, Cellules cultivées, Humains, Modèles biologiques, Souris, Techniques de knock-down de gènes.
English descriptors
- KwdEn :
- Adaptor Proteins, Signal Transducing (antagonists & inhibitors), Adaptor Proteins, Signal Transducing (genetics), Adaptor Proteins, Signal Transducing (metabolism), Animals (MeSH), Antiviral Agents (pharmacology), Autophagy (drug effects), Caco-2 Cells (MeSH), Cells, Cultured (MeSH), Gene Knockdown Techniques (MeSH), Humans (MeSH), Mice (MeSH), Models, Biological (MeSH), Organoids (metabolism), Organoids (pathology), Organoids (virology), Phosphatidylinositol 3-Kinases (metabolism), Phosphoinositide-3 Kinase Inhibitors (MeSH), Phosphoproteins (antagonists & inhibitors), Phosphoproteins (genetics), Phosphoproteins (metabolism), Phosphorylation (drug effects), Proto-Oncogene Proteins c-akt (metabolism), Rotavirus (physiology), Rotavirus Infections (metabolism), Rotavirus Infections (pathology), Rotavirus Infections (virology), Signal Transduction (drug effects), TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (genetics), TOR Serine-Threonine Kinases (metabolism), Virus Replication (drug effects).
- MESH :
- chemical , antagonists & inhibitors : Adaptor Proteins, Signal Transducing, Phosphoproteins, TOR Serine-Threonine Kinases.
- chemical , genetics : Adaptor Proteins, Signal Transducing, Phosphoproteins, TOR Serine-Threonine Kinases.
- chemical , metabolism : Adaptor Proteins, Signal Transducing, Phosphoproteins, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Antiviral Agents.
- drug effects : Autophagy, Phosphorylation, Signal Transduction, Virus Replication.
- metabolism : Organoids, Phosphatidylinositol 3-Kinases, Rotavirus Infections.
- pathology : Organoids, Rotavirus Infections.
- physiology : Rotavirus.
- virology : Organoids, Rotavirus Infections.
- Animals, Caco-2 Cells, Cells, Cultured, Gene Knockdown Techniques, Humans, Mice, Models, Biological, Phosphoinositide-3 Kinase Inhibitors.
Abstract
Rotavirus infection is a major cause of severe dehydrating diarrhea in infants younger than 5 y old and in particular cases of immunocompromised patients irrespective to the age of the patients. Although vaccines have been developed, antiviral therapy is an important complement that cannot be substituted. Because of the lack of specific approved treatment, it is urgent to facilitate the cascade of further understanding of the infection biology, identification of druggable targets and the final development of effective antiviral therapies. PI3K-Akt-mTOR signaling pathway plays a vital role in regulating the infection course of many viruses. In this study, we have dissected the effects of PI3K-Akt-mTOR signaling pathway on rotavirus infection using both conventional cell culture models and a 3D model of human primary intestinal organoids. We found that PI3K-Akt-mTOR signaling is essential in sustaining rotavirus infection. Thus, blocking the key elements of this pathway, including PI3K, mTOR and 4E-BP1, has resulted in potent anti-rotavirus activity. Importantly, a clinically used mTOR inhibitor, rapamycin, potently inhibited both experimental and patient-derived rotavirus strains. This effect involves 4E-BP1 mediated induction of autophagy, which in turn exerts anti-rotavirus effects. These results revealed new insights on rotavirus-host interactions and provided new avenues for antiviral drug development.
DOI: 10.1080/21505594.2017.1326443
PubMed: 28475412
PubMed Central: PMC5955461
Affiliations:
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R. China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>b Medical Faculty, Kunming University of Science and Technology , Kunming </wicri:regionArea><wicri:noRegion>Kunming </wicri:noRegion></affiliation></author><author><name sortKey="Cai, Xuepeng" sort="Cai, Xuepeng" uniqKey="Cai X" first="Xuepeng" last="Cai">Xuepeng Cai</name><affiliation wicri:level="1"><nlm:affiliation>c State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS) , Lanzhou , P. R. China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>c State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS) , Lanzhou </wicri:regionArea><wicri:noRegion>Lanzhou </wicri:noRegion></affiliation></author><author><name sortKey="Xiao, Shaobo" sort="Xiao, Shaobo" uniqKey="Xiao S" first="Shaobo" last="Xiao">Shaobo Xiao</name><affiliation wicri:level="1"><nlm:affiliation>d State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University , Wuhan , P. R. China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>d State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University , Wuhan </wicri:regionArea><wicri:noRegion>Wuhan </wicri:noRegion></affiliation></author><author><name sortKey="Peppelenbosch, Maikel P" sort="Peppelenbosch, Maikel P" uniqKey="Peppelenbosch M" first="Maikel P" last="Peppelenbosch">Maikel P. Peppelenbosch</name><affiliation wicri:level="1"><nlm:affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam </wicri:regionArea><wicri:noRegion>Rotterdam </wicri:noRegion></affiliation></author><author><name sortKey="Pan, Qiuwei" sort="Pan, Qiuwei" uniqKey="Pan Q" first="Qiuwei" last="Pan">Qiuwei Pan</name><affiliation wicri:level="1"><nlm:affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam </wicri:regionArea><wicri:noRegion>Rotterdam </wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:28475412</idno><idno type="pmid">28475412</idno><idno type="doi">10.1080/21505594.2017.1326443</idno><idno type="pmc">PMC5955461</idno><idno type="wicri:Area/Main/Corpus">000819</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000819</idno><idno type="wicri:Area/Main/Curation">000819</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000819</idno><idno type="wicri:Area/Main/Exploration">000819</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">PI3K-Akt-mTOR axis sustains rotavirus infection via the 4E-BP1 mediated autophagy pathway and represents an antiviral target.</title><author><name sortKey="Yin, Yuebang" sort="Yin, Yuebang" uniqKey="Yin Y" first="Yuebang" last="Yin">Yuebang Yin</name><affiliation wicri:level="1"><nlm:affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam </wicri:regionArea><wicri:noRegion>Rotterdam </wicri:noRegion></affiliation></author><author><name sortKey="Dang, Wen" sort="Dang, Wen" uniqKey="Dang W" first="Wen" last="Dang">Wen Dang</name><affiliation wicri:level="1"><nlm:affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam </wicri:regionArea><wicri:noRegion>Rotterdam </wicri:noRegion></affiliation></author><author><name sortKey="Zhou, Xinying" sort="Zhou, Xinying" uniqKey="Zhou X" first="Xinying" last="Zhou">Xinying Zhou</name><affiliation wicri:level="1"><nlm:affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam </wicri:regionArea><wicri:noRegion>Rotterdam </wicri:noRegion></affiliation></author><author><name sortKey="Xu, Lei" sort="Xu, Lei" uniqKey="Xu L" first="Lei" last="Xu">Lei Xu</name><affiliation wicri:level="1"><nlm:affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam </wicri:regionArea><wicri:noRegion>Rotterdam </wicri:noRegion></affiliation></author><author><name sortKey="Wang, Wenshi" sort="Wang, Wenshi" uniqKey="Wang W" first="Wenshi" last="Wang">Wenshi Wang</name><affiliation wicri:level="1"><nlm:affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam </wicri:regionArea><wicri:noRegion>Rotterdam </wicri:noRegion></affiliation></author><author><name sortKey="Cao, Wanlu" sort="Cao, Wanlu" uniqKey="Cao W" first="Wanlu" last="Cao">Wanlu Cao</name><affiliation wicri:level="1"><nlm:affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam </wicri:regionArea><wicri:noRegion>Rotterdam </wicri:noRegion></affiliation></author><author><name sortKey="Chen, Sunrui" sort="Chen, Sunrui" uniqKey="Chen S" first="Sunrui" last="Chen">Sunrui Chen</name><affiliation wicri:level="1"><nlm:affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam </wicri:regionArea><wicri:noRegion>Rotterdam </wicri:noRegion></affiliation></author><author><name sortKey="Su, Junhong" sort="Su, Junhong" uniqKey="Su J" first="Junhong" last="Su">Junhong Su</name><affiliation wicri:level="1"><nlm:affiliation>b Medical Faculty, Kunming University of Science and Technology , Kunming , P. R. China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>b Medical Faculty, Kunming University of Science and Technology , Kunming </wicri:regionArea><wicri:noRegion>Kunming </wicri:noRegion></affiliation></author><author><name sortKey="Cai, Xuepeng" sort="Cai, Xuepeng" uniqKey="Cai X" first="Xuepeng" last="Cai">Xuepeng Cai</name><affiliation wicri:level="1"><nlm:affiliation>c State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS) , Lanzhou , P. R. China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>c State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS) , Lanzhou </wicri:regionArea><wicri:noRegion>Lanzhou </wicri:noRegion></affiliation></author><author><name sortKey="Xiao, Shaobo" sort="Xiao, Shaobo" uniqKey="Xiao S" first="Shaobo" last="Xiao">Shaobo Xiao</name><affiliation wicri:level="1"><nlm:affiliation>d State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University , Wuhan , P. R. China.</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>d State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University , Wuhan </wicri:regionArea><wicri:noRegion>Wuhan </wicri:noRegion></affiliation></author><author><name sortKey="Peppelenbosch, Maikel P" sort="Peppelenbosch, Maikel P" uniqKey="Peppelenbosch M" first="Maikel P" last="Peppelenbosch">Maikel P. Peppelenbosch</name><affiliation wicri:level="1"><nlm:affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam </wicri:regionArea><wicri:noRegion>Rotterdam </wicri:noRegion></affiliation></author><author><name sortKey="Pan, Qiuwei" sort="Pan, Qiuwei" uniqKey="Pan Q" first="Qiuwei" last="Pan">Qiuwei Pan</name><affiliation wicri:level="1"><nlm:affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam </wicri:regionArea><wicri:noRegion>Rotterdam </wicri:noRegion></affiliation></author></analytic><series><title level="j">Virulence</title><idno type="eISSN">2150-5608</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adaptor Proteins, Signal Transducing (antagonists & inhibitors)</term><term>Adaptor Proteins, Signal Transducing (genetics)</term><term>Adaptor Proteins, Signal Transducing (metabolism)</term><term>Animals (MeSH)</term><term>Antiviral Agents (pharmacology)</term><term>Autophagy (drug effects)</term><term>Caco-2 Cells (MeSH)</term><term>Cells, Cultured (MeSH)</term><term>Gene Knockdown Techniques (MeSH)</term><term>Humans (MeSH)</term><term>Mice (MeSH)</term><term>Models, Biological (MeSH)</term><term>Organoids (metabolism)</term><term>Organoids (pathology)</term><term>Organoids (virology)</term><term>Phosphatidylinositol 3-Kinases (metabolism)</term><term>Phosphoinositide-3 Kinase Inhibitors (MeSH)</term><term>Phosphoproteins (antagonists & inhibitors)</term><term>Phosphoproteins (genetics)</term><term>Phosphoproteins (metabolism)</term><term>Phosphorylation (drug effects)</term><term>Proto-Oncogene Proteins c-akt (metabolism)</term><term>Rotavirus (physiology)</term><term>Rotavirus Infections (metabolism)</term><term>Rotavirus Infections (pathology)</term><term>Rotavirus Infections (virology)</term><term>Signal Transduction (drug effects)</term><term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term><term>TOR Serine-Threonine Kinases (genetics)</term><term>TOR Serine-Threonine Kinases (metabolism)</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term><term>Antiviraux (pharmacologie)</term><term>Autophagie (effets des médicaments et des substances chimiques)</term><term>Cellules Caco-2 (MeSH)</term><term>Cellules cultivées (MeSH)</term><term>Humains (MeSH)</term><term>Infections à rotavirus (anatomopathologie)</term><term>Infections à rotavirus (métabolisme)</term><term>Infections à rotavirus (virologie)</term><term>Modèles biologiques (MeSH)</term><term>Organoïdes (anatomopathologie)</term><term>Organoïdes (métabolisme)</term><term>Organoïdes (virologie)</term><term>Phosphatidylinositol 3-kinases (métabolisme)</term><term>Phosphoprotéines (antagonistes et inhibiteurs)</term><term>Phosphoprotéines (génétique)</term><term>Phosphoprotéines (métabolisme)</term><term>Phosphorylation (effets des médicaments et des substances chimiques)</term><term>Protéines adaptatrices de la transduction du signal (antagonistes et inhibiteurs)</term><term>Protéines adaptatrices de la transduction du signal (génétique)</term><term>Protéines adaptatrices de la transduction du signal (métabolisme)</term><term>Protéines proto-oncogènes c-akt (métabolisme)</term><term>Rotavirus (physiologie)</term><term>Réplication virale (effets des médicaments et des substances chimiques)</term><term>Souris (MeSH)</term><term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term><term>Sérine-thréonine kinases TOR (génétique)</term><term>Sérine-thréonine kinases TOR (métabolisme)</term><term>Techniques de knock-down de gènes (MeSH)</term><term>Transduction du signal (effets des médicaments et des substances chimiques)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Adaptor Proteins, Signal Transducing</term><term>Phosphoproteins</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Adaptor Proteins, Signal Transducing</term><term>Phosphoproteins</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Adaptor Proteins, Signal Transducing</term><term>Phosphoproteins</term><term>Proto-Oncogene Proteins c-akt</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Infections à rotavirus</term><term>Organoïdes</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Phosphoprotéines</term><term>Protéines adaptatrices de la transduction du signal</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term><term>Phosphorylation</term><term>Signal Transduction</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Autophagie</term><term>Phosphorylation</term><term>Réplication virale</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Phosphoprotéines</term><term>Protéines adaptatrices de la transduction du signal</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Organoids</term><term>Phosphatidylinositol 3-Kinases</term><term>Rotavirus Infections</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Infections à rotavirus</term><term>Organoïdes</term><term>Phosphatidylinositol 3-kinases</term><term>Phosphoprotéines</term><term>Protéines adaptatrices de la transduction du signal</term><term>Protéines proto-oncogènes c-akt</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Organoids</term><term>Rotavirus Infections</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Rotavirus</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Rotavirus</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Infections à rotavirus</term><term>Organoïdes</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Organoids</term><term>Rotavirus Infections</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Caco-2 Cells</term><term>Cells, Cultured</term><term>Gene Knockdown Techniques</term><term>Humans</term><term>Mice</term><term>Models, Biological</term><term>Phosphoinositide-3 Kinase Inhibitors</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cellules Caco-2</term><term>Cellules cultivées</term><term>Humains</term><term>Modèles biologiques</term><term>Souris</term><term>Techniques de knock-down de gènes</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Rotavirus infection is a major cause of severe dehydrating diarrhea in infants younger than 5 y old and in particular cases of immunocompromised patients irrespective to the age of the patients. Although vaccines have been developed, antiviral therapy is an important complement that cannot be substituted. Because of the lack of specific approved treatment, it is urgent to facilitate the cascade of further understanding of the infection biology, identification of druggable targets and the final development of effective antiviral therapies. PI3K-Akt-mTOR signaling pathway plays a vital role in regulating the infection course of many viruses. In this study, we have dissected the effects of PI3K-Akt-mTOR signaling pathway on rotavirus infection using both conventional cell culture models and a 3D model of human primary intestinal organoids. We found that PI3K-Akt-mTOR signaling is essential in sustaining rotavirus infection. Thus, blocking the key elements of this pathway, including PI3K, mTOR and 4E-BP1, has resulted in potent anti-rotavirus activity. Importantly, a clinically used mTOR inhibitor, rapamycin, potently inhibited both experimental and patient-derived rotavirus strains. This effect involves 4E-BP1 mediated induction of autophagy, which in turn exerts anti-rotavirus effects. These results revealed new insights on rotavirus-host interactions and provided new avenues for antiviral drug development.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28475412</PMID><DateCompleted><Year>2018</Year><Month>11</Month><Day>27</Day></DateCompleted><DateRevised><Year>2019</Year><Month>12</Month><Day>10</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">2150-5608</ISSN><JournalIssue CitedMedium="Internet"><Volume>9</Volume><Issue>1</Issue><PubDate><Year>2018</Year><Month>01</Month><Day>01</Day></PubDate></JournalIssue><Title>Virulence</Title><ISOAbbreviation>Virulence</ISOAbbreviation></Journal><ArticleTitle>PI3K-Akt-mTOR axis sustains rotavirus infection via the 4E-BP1 mediated autophagy pathway and represents an antiviral target.</ArticleTitle><Pagination><MedlinePgn>83-98</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1080/21505594.2017.1326443</ELocationID><Abstract><AbstractText>Rotavirus infection is a major cause of severe dehydrating diarrhea in infants younger than 5 y old and in particular cases of immunocompromised patients irrespective to the age of the patients. Although vaccines have been developed, antiviral therapy is an important complement that cannot be substituted. Because of the lack of specific approved treatment, it is urgent to facilitate the cascade of further understanding of the infection biology, identification of druggable targets and the final development of effective antiviral therapies. PI3K-Akt-mTOR signaling pathway plays a vital role in regulating the infection course of many viruses. In this study, we have dissected the effects of PI3K-Akt-mTOR signaling pathway on rotavirus infection using both conventional cell culture models and a 3D model of human primary intestinal organoids. We found that PI3K-Akt-mTOR signaling is essential in sustaining rotavirus infection. Thus, blocking the key elements of this pathway, including PI3K, mTOR and 4E-BP1, has resulted in potent anti-rotavirus activity. Importantly, a clinically used mTOR inhibitor, rapamycin, potently inhibited both experimental and patient-derived rotavirus strains. This effect involves 4E-BP1 mediated induction of autophagy, which in turn exerts anti-rotavirus effects. These results revealed new insights on rotavirus-host interactions and provided new avenues for antiviral drug development.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Yin</LastName><ForeName>Yuebang</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dang</LastName><ForeName>Wen</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhou</LastName><ForeName>Xinying</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Xu</LastName><ForeName>Lei</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Wenshi</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cao</LastName><ForeName>Wanlu</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Sunrui</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Su</LastName><ForeName>Junhong</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>b Medical Faculty, Kunming University of Science and Technology , Kunming , P. R. China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cai</LastName><ForeName>Xuepeng</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>c State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS) , Lanzhou , P. R. China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Xiao</LastName><ForeName>Shaobo</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>d State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University , Wuhan , P. R. China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Peppelenbosch</LastName><ForeName>Maikel P</ForeName><Initials>MP</Initials><AffiliationInfo><Affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pan</LastName><ForeName>Qiuwei</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>a Department of Gastroenterology and Hepatology , Erasmus MC-University Medical Center , Rotterdam , The Netherlands.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>06</Month><Day>01</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Virulence</MedlineTA><NlmUniqueID>101531386</NlmUniqueID><ISSNLinking>2150-5594</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D048868">Adaptor Proteins, Signal Transducing</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C087000">EIF4EBP1 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000081082">Phosphoinositide-3 Kinase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010750">Phosphoproteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="C546842">MTOR protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D051057">Proto-Oncogene Proteins c-akt</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="CommentIn"><RefSource>Virulence. 2018 Jan 1;9(1):5-8</RefSource><PMID Version="1">28723236</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D048868" MajorTopicYN="N">Adaptor Proteins, Signal Transducing</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001343" MajorTopicYN="N">Autophagy</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018938" MajorTopicYN="N">Caco-2 Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002478" MajorTopicYN="N">Cells, Cultured</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D055785" MajorTopicYN="N">Gene Knockdown Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008954" MajorTopicYN="N">Models, Biological</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009940" MajorTopicYN="N">Organoids</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName><QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019869" MajorTopicYN="N">Phosphatidylinositol 3-Kinases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000081082" MajorTopicYN="N">Phosphoinositide-3 Kinase Inhibitors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010750" MajorTopicYN="N">Phosphoproteins</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010766" MajorTopicYN="N">Phosphorylation</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051057" MajorTopicYN="N">Proto-Oncogene Proteins c-akt</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012401" MajorTopicYN="N">Rotavirus</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012400" MajorTopicYN="N">Rotavirus Infections</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName><QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014779" MajorTopicYN="N">Virus Replication</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">PI3K-Akt-mTOR-4E-BP1 pathway</Keyword><Keyword MajorTopicYN="Y">autophagy</Keyword><Keyword MajorTopicYN="Y">intestinal organoids</Keyword><Keyword MajorTopicYN="Y">rotavirus</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate 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Chine</li></country></list><tree><country name="Pays-Bas"><noRegion><name sortKey="Yin, Yuebang" sort="Yin, Yuebang" uniqKey="Yin Y" first="Yuebang" last="Yin">Yuebang Yin</name></noRegion><name sortKey="Cao, Wanlu" sort="Cao, Wanlu" uniqKey="Cao W" first="Wanlu" last="Cao">Wanlu Cao</name><name sortKey="Chen, Sunrui" sort="Chen, Sunrui" uniqKey="Chen S" first="Sunrui" last="Chen">Sunrui Chen</name><name sortKey="Dang, Wen" sort="Dang, Wen" uniqKey="Dang W" first="Wen" last="Dang">Wen Dang</name><name sortKey="Pan, Qiuwei" sort="Pan, Qiuwei" uniqKey="Pan Q" first="Qiuwei" last="Pan">Qiuwei Pan</name><name sortKey="Peppelenbosch, Maikel P" sort="Peppelenbosch, Maikel P" uniqKey="Peppelenbosch M" first="Maikel P" last="Peppelenbosch">Maikel P. Peppelenbosch</name><name sortKey="Wang, Wenshi" sort="Wang, Wenshi" uniqKey="Wang W" first="Wenshi" last="Wang">Wenshi Wang</name><name sortKey="Xu, Lei" sort="Xu, Lei" uniqKey="Xu L" first="Lei" last="Xu">Lei Xu</name><name sortKey="Zhou, Xinying" sort="Zhou, Xinying" uniqKey="Zhou X" first="Xinying" last="Zhou">Xinying Zhou</name></country><country name="République populaire de Chine"><noRegion><name sortKey="Su, Junhong" sort="Su, Junhong" uniqKey="Su J" first="Junhong" last="Su">Junhong Su</name></noRegion><name sortKey="Cai, Xuepeng" sort="Cai, Xuepeng" uniqKey="Cai X" first="Xuepeng" last="Cai">Xuepeng Cai</name><name sortKey="Xiao, Shaobo" sort="Xiao, Shaobo" uniqKey="Xiao S" first="Shaobo" last="Xiao">Shaobo Xiao</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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