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Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin

Identifieur interne : 004458 ( Main/Exploration ); précédent : 004457; suivant : 004459

Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin

Auteurs : Dale L. Barnard [États-Unis] ; Craig W. Day [États-Unis] ; Kevin Bailey [États-Unis] ; Matthew Heiner [États-Unis] ; Robert Montgomery [États-Unis] ; Larry Lauridsen [États-Unis] ; Scott Winslow [États-Unis] ; Justin Hoopes [États-Unis] ; Joseph K.-K. Li [États-Unis] ; Jongdae Lee [États-Unis] ; Dennis A. Carson [États-Unis] ; Howard B. Cottam [États-Unis] ; Robert W. Sidwell [États-Unis]

Source :

RBID : Pascal:06-0398673

Descripteurs français

English descriptors

Abstract

Because of the conflicting data concerning the SARS-CoV inhibitory efficacy of ribavirin, an inosine monophosphate (IMP) dehydrogenase inhibitor, studies were done to evaluate the efficacy of ribavirin and other IMP dehydrogenase inhibitors (5-ethynyl- 1-β-D-ribofuranosylimidazole-4-carboxamide (EICAR), mizoribine, and mycophenolic acid) in preventing viral replication in the lungs of BALB/c mice, a replication model for severe acute respiratory syndrome (SARS) infections (Subbarao, K., McAuliffe, J., Vogel, L., Fahle, G., Fischer, S., Tatti, K., Packard, M., Shieh, W.J., Zaki, S., Murphy, B., 2004. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in the respiratory tract of mice. J. Virol. 78, 3572-3577). Ribavirin given at 75 mg/kg 4 h prior to virus exposure and then given twice daily for 3 days beginning at day 0 was found to increase virus lung titers and extend the length of time that virus could be detected in the lungs of mice. Other IMP dehydrogenase inhibitors administered near maximum tolerated doses using the same dosing regimen as for ribavirin were found to slightly enhance virus replication in the lungs. In addition, ribavirin treatment seemed also to promote the production of pro-inflammatory cytokines 4 days after cessation of treatment, although after 3 days of treatment ribavirin inhibited pro-inflammatory cytokine production in infected mice, significantly reducing the levels of the cytokines IL-1α, interleukin-5 (IL-5), monocyte chemotactic protein-1 (MCP-1), and granulocyte-macrophage colony stimulating factor (GM-CSF). These findings suggest that ribavirin may actually contribute to the pathogenesis of SARS-CoV by prolonging and/or enhancing viral replication in the lungs. By not inhibiting viral replication in the lungs of infected mice, ribavirin treatment may have provided a continual source of stimulation for the inflammatory response thought to contribute to the pathogenesis of the infection. Our data do not support the use of ribavirin or other IMP dehydrogenase inhibitors for treating SARS infections in humans.


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<s1>Moores Cancer Center 0820, University of California, San Diego, 3855 Health Sciences Drive</s1>
<s2>La Jolla, CA 92093-0820</s2>
<s3>USA</s3>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName>
<region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Sidwell, Robert W" sort="Sidwell, Robert W" uniqKey="Sidwell R" first="Robert W." last="Sidwell">Robert W. Sidwell</name>
<affiliation wicri:level="2">
<inist:fA14 i1="01">
<s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1>
<s2>Logan, UT 84322-5600</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>13 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName>
<region type="state">Utah</region>
</placeName>
</affiliation>
</author>
</analytic>
<series>
<title level="j" type="main">Antiviral research</title>
<title level="j" type="abbreviated">Antivir. res.</title>
<idno type="ISSN">0166-3542</idno>
<imprint>
<date when="2006">2006</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt>
<title level="j" type="main">Antiviral research</title>
<title level="j" type="abbreviated">Antivir. res.</title>
<idno type="ISSN">0166-3542</idno>
</seriesStmt>
</fileDesc>
<profileDesc>
<textClass>
<keywords scheme="KwdEn" xml:lang="en">
<term>Animal</term>
<term>Animals</term>
<term>Antiviral</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Caco-2 Cells</term>
<term>Cell Survival (drug effects)</term>
<term>Chlorocebus aethiops</term>
<term>Coronavirus</term>
<term>Cytokines (metabolism)</term>
<term>Cytopathogenic Effect, Viral (drug effects)</term>
<term>Female</term>
<term>Humans</term>
<term>IMP Dehydrogenase (antagonists & inhibitors)</term>
<term>IMP dehydrogenase</term>
<term>Infectivity</term>
<term>Inhibitor</term>
<term>Lung (pathology)</term>
<term>Lung (virology)</term>
<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Mouse</term>
<term>Mycophenolic Acid (pharmacology)</term>
<term>Oligonucleotide Array Sequence Analysis</term>
<term>Ribavirin</term>
<term>Ribavirin (pharmacology)</term>
<term>Ribonucleosides (pharmacology)</term>
<term>SARS Virus (drug effects)</term>
<term>SARS Virus (enzymology)</term>
<term>SARS Virus (pathogenicity)</term>
<term>SARS Virus (physiology)</term>
<term>Severe Acute Respiratory Syndrome (drug therapy)</term>
<term>Severe Acute Respiratory Syndrome (virology)</term>
<term>Severe acute respiratory syndrome</term>
<term>Specific Pathogen-Free Organisms</term>
<term>Vero Cells</term>
<term>Virus Replication (drug effects)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Acide mycophénolique (pharmacologie)</term>
<term>Animaux</term>
<term>Antiviraux (pharmacologie)</term>
<term>Cellules Caco-2</term>
<term>Cellules Vero</term>
<term>Cytokines (métabolisme)</term>
<term>Effet cytopathogène viral ()</term>
<term>Femelle</term>
<term>Humains</term>
<term>IMP dehydrogenase (antagonistes et inhibiteurs)</term>
<term>Organismes exempts d'organismes pathogènes spécifiques</term>
<term>Poumon (anatomopathologie)</term>
<term>Poumon (virologie)</term>
<term>Ribavirine (pharmacologie)</term>
<term>Ribonucléosides (pharmacologie)</term>
<term>Réplication virale ()</term>
<term>Souris</term>
<term>Souris de lignée BALB C</term>
<term>Survie cellulaire ()</term>
<term>Syndrome respiratoire aigu sévère (traitement médicamenteux)</term>
<term>Syndrome respiratoire aigu sévère (virologie)</term>
<term>Séquençage par oligonucléotides en batterie</term>
<term>Virus du SRAS ()</term>
<term>Virus du SRAS (enzymologie)</term>
<term>Virus du SRAS (pathogénicité)</term>
<term>Virus du SRAS (physiologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en">
<term>IMP Dehydrogenase</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en">
<term>Cytokines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en">
<term>Antiviral Agents</term>
<term>Mycophenolic Acid</term>
<term>Ribavirin</term>
<term>Ribonucleosides</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr">
<term>Poumon</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr">
<term>IMP dehydrogenase</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en">
<term>Cell Survival</term>
<term>Cytopathogenic Effect, Viral</term>
<term>SARS Virus</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en">
<term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr">
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en">
<term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Cytokines</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="pathology" xml:lang="en">
<term>Lung</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr">
<term>Acide mycophénolique</term>
<term>Antiviraux</term>
<term>Ribavirine</term>
<term>Ribonucléosides</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr">
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en">
<term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr">
<term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr">
<term>Poumon</term>
<term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en">
<term>Lung</term>
<term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Animals</term>
<term>Caco-2 Cells</term>
<term>Chlorocebus aethiops</term>
<term>Female</term>
<term>Humans</term>
<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Oligonucleotide Array Sequence Analysis</term>
<term>Specific Pathogen-Free Organisms</term>
<term>Vero Cells</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr">
<term>Animaux</term>
<term>Cellules Caco-2</term>
<term>Cellules Vero</term>
<term>Effet cytopathogène viral</term>
<term>Femelle</term>
<term>Humains</term>
<term>Organismes exempts d'organismes pathogènes spécifiques</term>
<term>Pouvoir infectant</term>
<term>Antiviral</term>
<term>Réplication virale</term>
<term>Souris</term>
<term>Souris de lignée BALB C</term>
<term>Survie cellulaire</term>
<term>Syndrome respiratoire aigu sévère</term>
<term>Animal</term>
<term>Souris</term>
<term>IMP dehydrogenase</term>
<term>Inhibiteur</term>
<term>Ribavirine</term>
<term>Coronavirus</term>
<term>Séquençage par oligonucléotides en batterie</term>
<term>Virus du SRAS</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">Because of the conflicting data concerning the SARS-CoV inhibitory efficacy of ribavirin, an inosine monophosphate (IMP) dehydrogenase inhibitor, studies were done to evaluate the efficacy of ribavirin and other IMP dehydrogenase inhibitors (5-ethynyl- 1-β-D-ribofuranosylimidazole-4-carboxamide (EICAR), mizoribine, and mycophenolic acid) in preventing viral replication in the lungs of BALB/c mice, a replication model for severe acute respiratory syndrome (SARS) infections (Subbarao, K., McAuliffe, J., Vogel, L., Fahle, G., Fischer, S., Tatti, K., Packard, M., Shieh, W.J., Zaki, S., Murphy, B., 2004. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in the respiratory tract of mice. J. Virol. 78, 3572-3577). Ribavirin given at 75 mg/kg 4 h prior to virus exposure and then given twice daily for 3 days beginning at day 0 was found to increase virus lung titers and extend the length of time that virus could be detected in the lungs of mice. Other IMP dehydrogenase inhibitors administered near maximum tolerated doses using the same dosing regimen as for ribavirin were found to slightly enhance virus replication in the lungs. In addition, ribavirin treatment seemed also to promote the production of pro-inflammatory cytokines 4 days after cessation of treatment, although after 3 days of treatment ribavirin inhibited pro-inflammatory cytokine production in infected mice, significantly reducing the levels of the cytokines IL-1α, interleukin-5 (IL-5), monocyte chemotactic protein-1 (MCP-1), and granulocyte-macrophage colony stimulating factor (GM-CSF). These findings suggest that ribavirin may actually contribute to the pathogenesis of SARS-CoV by prolonging and/or enhancing viral replication in the lungs. By not inhibiting viral replication in the lungs of infected mice, ribavirin treatment may have provided a continual source of stimulation for the inflammatory response thought to contribute to the pathogenesis of the infection. Our data do not support the use of ribavirin or other IMP dehydrogenase inhibitors for treating SARS infections in humans.</div>
</front>
</TEI>
<affiliations>
<list>
<country>
<li>États-Unis</li>
</country>
<region>
<li>Californie</li>
<li>Utah</li>
</region>
</list>
<tree>
<country name="États-Unis">
<region name="Utah">
<name sortKey="Barnard, Dale L" sort="Barnard, Dale L" uniqKey="Barnard D" first="Dale L." last="Barnard">Dale L. Barnard</name>
</region>
<name sortKey="Bailey, Kevin" sort="Bailey, Kevin" uniqKey="Bailey K" first="Kevin" last="Bailey">Kevin Bailey</name>
<name sortKey="Carson, Dennis A" sort="Carson, Dennis A" uniqKey="Carson D" first="Dennis A." last="Carson">Dennis A. Carson</name>
<name sortKey="Cottam, Howard B" sort="Cottam, Howard B" uniqKey="Cottam H" first="Howard B." last="Cottam">Howard B. Cottam</name>
<name sortKey="Day, Craig W" sort="Day, Craig W" uniqKey="Day C" first="Craig W." last="Day">Craig W. Day</name>
<name sortKey="Heiner, Matthew" sort="Heiner, Matthew" uniqKey="Heiner M" first="Matthew" last="Heiner">Matthew Heiner</name>
<name sortKey="Hoopes, Justin" sort="Hoopes, Justin" uniqKey="Hoopes J" first="Justin" last="Hoopes">Justin Hoopes</name>
<name sortKey="Lauridsen, Larry" sort="Lauridsen, Larry" uniqKey="Lauridsen L" first="Larry" last="Lauridsen">Larry Lauridsen</name>
<name sortKey="Lee, Jongdae" sort="Lee, Jongdae" uniqKey="Lee J" first="Jongdae" last="Lee">Jongdae Lee</name>
<name sortKey="Li, Joseph K K" sort="Li, Joseph K K" uniqKey="Li J" first="Joseph K.-K." last="Li">Joseph K.-K. Li</name>
<name sortKey="Montgomery, Robert" sort="Montgomery, Robert" uniqKey="Montgomery R" first="Robert" last="Montgomery">Robert Montgomery</name>
<name sortKey="Sidwell, Robert W" sort="Sidwell, Robert W" uniqKey="Sidwell R" first="Robert W." last="Sidwell">Robert W. Sidwell</name>
<name sortKey="Winslow, Scott" sort="Winslow, Scott" uniqKey="Winslow S" first="Scott" last="Winslow">Scott Winslow</name>
</country>
</tree>
</affiliations>
</record>

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