Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a post-endosomal level.
Identifieur interne : 003167 ( Main/Exploration ); précédent : 003166; suivant : 003168Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a post-endosomal level.
Auteurs : Konrad Stadler [Italie] ; Huy Riem Ha ; Vincenzo Ciminale ; Carlo Spirli ; Giulietta Saletti ; Marco Schiavon ; Daniela Bruttomesso ; Laurent Bigler ; Ferenc Follath ; Andrea Pettenazzo ; Aldo BaritussioSource :
- American journal of respiratory cell and molecular biology [ 1535-4989 ] ; 2008.
Descripteurs français
- KwdFr :
- Amiodarone (pharmacocinétique), Amiodarone (pharmacologie), Animaux, Antiviraux (pharmacocinétique), Antiviraux (pharmacologie), Cathepsine L, Cathepsines (métabolisme), Cellules Vero, Cysteine endopeptidases (métabolisme), Cytoplasme (), Cytoplasme (métabolisme), Endosomes (), Endosomes (métabolisme), Glycoprotéine de spicule des coronavirus, Glycoprotéines membranaires (métabolisme), Humains, Isotopes de l'iode (), Macrophages alvéolaires (), Macrophages alvéolaires (métabolisme), Macrophages alvéolaires (virologie), Membrane cellulaire (), Membrane cellulaire (métabolisme), Protéines de l'enveloppe virale (métabolisme), Syndrome respiratoire aigu sévère (métabolisme), Syndrome respiratoire aigu sévère (traitement médicamenteux), Syndrome respiratoire aigu sévère (virologie), Vacuoles (), Vacuoles (métabolisme), Virus du SRAS (), Virus du SRAS (physiologie).
- MESH :
- métabolisme : Cathepsines, Cysteine endopeptidases, Cytoplasme, Endosomes, Glycoprotéines membranaires, Macrophages alvéolaires, Membrane cellulaire, Protéines de l'enveloppe virale, Syndrome respiratoire aigu sévère, Vacuoles.
- pharmacocinétique : Amiodarone, Antiviraux.
- pharmacologie : Amiodarone, Antiviraux.
- physiologie : Virus du SRAS.
- traitement médicamenteux : Syndrome respiratoire aigu sévère.
- virologie : Macrophages alvéolaires, Syndrome respiratoire aigu sévère.
- Animaux, Cathepsine L, Cellules Vero, Cytoplasme, Endosomes, Glycoprotéine de spicule des coronavirus, Humains, Isotopes de l'iode, Macrophages alvéolaires, Membrane cellulaire, Vacuoles, Virus du SRAS.
English descriptors
- KwdEn :
- Amiodarone (pharmacokinetics), Amiodarone (pharmacology), Animals, Antiviral Agents (pharmacokinetics), Antiviral Agents (pharmacology), Cathepsin L, Cathepsins (metabolism), Cell Membrane (drug effects), Cell Membrane (metabolism), Chlorocebus aethiops, Cysteine Endopeptidases (metabolism), Cytoplasm (drug effects), Cytoplasm (metabolism), Endosomes (drug effects), Endosomes (metabolism), Humans, Iodine Isotopes (chemistry), Macrophages, Alveolar (drug effects), Macrophages, Alveolar (metabolism), Macrophages, Alveolar (virology), Membrane Glycoproteins (metabolism), SARS Virus (drug effects), SARS Virus (physiology), Severe Acute Respiratory Syndrome (drug therapy), Severe Acute Respiratory Syndrome (metabolism), Severe Acute Respiratory Syndrome (virology), Spike Glycoprotein, Coronavirus, Vacuoles (drug effects), Vacuoles (metabolism), Vero Cells, Viral Envelope Proteins (metabolism).
- MESH :
- chemical , chemistry : Iodine Isotopes.
- chemical , metabolism : Cathepsins, Cysteine Endopeptidases, Membrane Glycoproteins, Viral Envelope Proteins.
- chemical , pharmacokinetics : Amiodarone, Antiviral Agents.
- chemical , pharmacology : Amiodarone, Antiviral Agents.
- drug effects : Cell Membrane, Cytoplasm, Endosomes, Macrophages, Alveolar, SARS Virus, Vacuoles.
- drug therapy : Severe Acute Respiratory Syndrome.
- metabolism : Cell Membrane, Cytoplasm, Endosomes, Macrophages, Alveolar, Severe Acute Respiratory Syndrome, Vacuoles.
- physiology : SARS Virus.
- virology : Macrophages, Alveolar, Severe Acute Respiratory Syndrome.
- Animals, Cathepsin L, Chlorocebus aethiops, Humans, Spike Glycoprotein, Coronavirus, Vero Cells.
Abstract
Amiodarone interferes with the endocytic pathway, inhibits proteolysis, and causes the formation of vacuoles, but uptake and intracellular distribution of the drug, origin of vacuoles, and functional consequences of amiodarone accumulation remain unclear. Our objective was to study amiodarone uptake, clarify the origin of vacuoles, and investigate the effect of amiodarone on the life cycle of the coronavirus responsible for the Severe Acute Respiratory Syndrome (SARS), which, to enter cells, relies on the proteolytic cleavage of a viral spike protein by the endosomal proteinase cathepsin L. Using alveolar macrophages, we studied uptake of (125)I-amiodarone and (125)I-B2, an analog lacking the lateral group diethylamino-beta-ethoxy, and analyzed the effects of amiodarone on the distribution of endosomal markers and on the uptake of an acidotropic dye. Furthermore, using Vero cells, we tested the impact of amiodarone on the in vitro spreading of the SARS coronavirus. We found that (1) amiodarone associates with different cell membranes and accumulates in acidic organelles; (2) the diethylamino-beta-ethoxy group is an important determinant of uptake; (3) vacuoles forming upon exposure to amiodarone are enlarged late endosomes; (4) amiodarone inhibits the spreading in vitro of SARS coronavirus; and (5) trypsin cleavage of the viral spike protein before infection, which permits virus entry through the plasma membrane, does not impair amiodarone antiviral activity. We conclude that amiodarone alters late compartments of the endocytic pathway and inhibits SARS coronavirus infection by acting after the transit of the virus through endosomes.
DOI: 10.1165/rcmb.2007-0217OC
PubMed: 18314540
Affiliations:
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Le document en format XML
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<term>Amiodarone (pharmacology)</term>
<term>Animals</term>
<term>Antiviral Agents (pharmacokinetics)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Cathepsin L</term>
<term>Cathepsins (metabolism)</term>
<term>Cell Membrane (drug effects)</term>
<term>Cell Membrane (metabolism)</term>
<term>Chlorocebus aethiops</term>
<term>Cysteine Endopeptidases (metabolism)</term>
<term>Cytoplasm (drug effects)</term>
<term>Cytoplasm (metabolism)</term>
<term>Endosomes (drug effects)</term>
<term>Endosomes (metabolism)</term>
<term>Humans</term>
<term>Iodine Isotopes (chemistry)</term>
<term>Macrophages, Alveolar (drug effects)</term>
<term>Macrophages, Alveolar (metabolism)</term>
<term>Macrophages, Alveolar (virology)</term>
<term>Membrane Glycoproteins (metabolism)</term>
<term>SARS Virus (drug effects)</term>
<term>SARS Virus (physiology)</term>
<term>Severe Acute Respiratory Syndrome (drug therapy)</term>
<term>Severe Acute Respiratory Syndrome (metabolism)</term>
<term>Severe Acute Respiratory Syndrome (virology)</term>
<term>Spike Glycoprotein, Coronavirus</term>
<term>Vacuoles (drug effects)</term>
<term>Vacuoles (metabolism)</term>
<term>Vero Cells</term>
<term>Viral Envelope Proteins (metabolism)</term>
</keywords>
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<term>Amiodarone (pharmacologie)</term>
<term>Animaux</term>
<term>Antiviraux (pharmacocinétique)</term>
<term>Antiviraux (pharmacologie)</term>
<term>Cathepsine L</term>
<term>Cathepsines (métabolisme)</term>
<term>Cellules Vero</term>
<term>Cysteine endopeptidases (métabolisme)</term>
<term>Cytoplasme ()</term>
<term>Cytoplasme (métabolisme)</term>
<term>Endosomes ()</term>
<term>Endosomes (métabolisme)</term>
<term>Glycoprotéine de spicule des coronavirus</term>
<term>Glycoprotéines membranaires (métabolisme)</term>
<term>Humains</term>
<term>Isotopes de l'iode ()</term>
<term>Macrophages alvéolaires ()</term>
<term>Macrophages alvéolaires (métabolisme)</term>
<term>Macrophages alvéolaires (virologie)</term>
<term>Membrane cellulaire ()</term>
<term>Membrane cellulaire (métabolisme)</term>
<term>Protéines de l'enveloppe virale (métabolisme)</term>
<term>Syndrome respiratoire aigu sévère (métabolisme)</term>
<term>Syndrome respiratoire aigu sévère (traitement médicamenteux)</term>
<term>Syndrome respiratoire aigu sévère (virologie)</term>
<term>Vacuoles ()</term>
<term>Vacuoles (métabolisme)</term>
<term>Virus du SRAS ()</term>
<term>Virus du SRAS (physiologie)</term>
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<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Iodine Isotopes</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cathepsins</term>
<term>Cysteine Endopeptidases</term>
<term>Membrane Glycoproteins</term>
<term>Viral Envelope Proteins</term>
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<term>Antiviral Agents</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Amiodarone</term>
<term>Antiviral Agents</term>
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<term>Cytoplasm</term>
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<term>Macrophages, Alveolar</term>
<term>SARS Virus</term>
<term>Vacuoles</term>
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<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term>
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<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cell Membrane</term>
<term>Cytoplasm</term>
<term>Endosomes</term>
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<term>Severe Acute Respiratory Syndrome</term>
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<term>Cysteine endopeptidases</term>
<term>Cytoplasme</term>
<term>Endosomes</term>
<term>Glycoprotéines membranaires</term>
<term>Macrophages alvéolaires</term>
<term>Membrane cellulaire</term>
<term>Protéines de l'enveloppe virale</term>
<term>Syndrome respiratoire aigu sévère</term>
<term>Vacuoles</term>
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<term>Antiviraux</term>
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<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Amiodarone</term>
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<term>Cathepsin L</term>
<term>Chlorocebus aethiops</term>
<term>Humans</term>
<term>Spike Glycoprotein, Coronavirus</term>
<term>Vero Cells</term>
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<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Cathepsine L</term>
<term>Cellules Vero</term>
<term>Cytoplasme</term>
<term>Endosomes</term>
<term>Glycoprotéine de spicule des coronavirus</term>
<term>Humains</term>
<term>Isotopes de l'iode</term>
<term>Macrophages alvéolaires</term>
<term>Membrane cellulaire</term>
<term>Vacuoles</term>
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<front><div type="abstract" xml:lang="en">Amiodarone interferes with the endocytic pathway, inhibits proteolysis, and causes the formation of vacuoles, but uptake and intracellular distribution of the drug, origin of vacuoles, and functional consequences of amiodarone accumulation remain unclear. Our objective was to study amiodarone uptake, clarify the origin of vacuoles, and investigate the effect of amiodarone on the life cycle of the coronavirus responsible for the Severe Acute Respiratory Syndrome (SARS), which, to enter cells, relies on the proteolytic cleavage of a viral spike protein by the endosomal proteinase cathepsin L. Using alveolar macrophages, we studied uptake of (125)I-amiodarone and (125)I-B2, an analog lacking the lateral group diethylamino-beta-ethoxy, and analyzed the effects of amiodarone on the distribution of endosomal markers and on the uptake of an acidotropic dye. Furthermore, using Vero cells, we tested the impact of amiodarone on the in vitro spreading of the SARS coronavirus. We found that (1) amiodarone associates with different cell membranes and accumulates in acidic organelles; (2) the diethylamino-beta-ethoxy group is an important determinant of uptake; (3) vacuoles forming upon exposure to amiodarone are enlarged late endosomes; (4) amiodarone inhibits the spreading in vitro of SARS coronavirus; and (5) trypsin cleavage of the viral spike protein before infection, which permits virus entry through the plasma membrane, does not impair amiodarone antiviral activity. We conclude that amiodarone alters late compartments of the endocytic pathway and inhibits SARS coronavirus infection by acting after the transit of the virus through endosomes.</div>
</front>
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<affiliations><list><country><li>Italie</li>
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<tree><noCountry><name sortKey="Baritussio, Aldo" sort="Baritussio, Aldo" uniqKey="Baritussio A" first="Aldo" last="Baritussio">Aldo Baritussio</name>
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<country name="Italie"><noRegion><name sortKey="Stadler, Konrad" sort="Stadler, Konrad" uniqKey="Stadler K" first="Konrad" last="Stadler">Konrad Stadler</name>
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