Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity.
Identifieur interne : 001D40 ( Main/Exploration ); précédent : 001D39; suivant : 001D41Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity.
Auteurs : Vineet D. Menachery [États-Unis] ; Boyd L. Yount ; Laurence Josset ; Lisa E. Gralinski ; Trevor Scobey ; Sudhakar Agnihothram ; Michael G. Katze ; Ralph S. BaricSource :
- Journal of virology [ 1098-5514 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, DEAD-box RNA helicases (génétique), DEAD-box RNA helicases (métabolisme), Femelle, Humains, Hélicase IFIH1 inductrice de l'interféron, Methyltransferases (), Methyltransferases (génétique), Methyltransferases (métabolisme), Motifs d'acides aminés, Mutation, Mâle, Protéines de liaison à l'ARN, Protéines de transport (génétique), Protéines de transport (métabolisme), Protéines virales non structurales (), Protéines virales non structurales (génétique), Protéines virales non structurales (métabolisme), Réplication virale, Souris, Souris de lignée BALB C, Souris de lignée C57BL, Syndrome respiratoire aigu sévère (génétique), Syndrome respiratoire aigu sévère (métabolisme), Syndrome respiratoire aigu sévère (virologie), Virulence, Virus du SRAS (enzymologie), Virus du SRAS (génétique), Virus du SRAS (pathogénicité), Virus du SRAS (physiologie).
- MESH :
- enzymologie : Virus du SRAS.
- génétique : DEAD-box RNA helicases, Methyltransferases, Protéines de transport, Protéines virales non structurales, Syndrome respiratoire aigu sévère, Virus du SRAS.
- métabolisme : DEAD-box RNA helicases, Methyltransferases, Protéines de transport, Protéines virales non structurales, Syndrome respiratoire aigu sévère.
- pathogénicité : Virus du SRAS.
- physiologie : Virus du SRAS.
- virologie : Syndrome respiratoire aigu sévère.
- Animaux, Femelle, Humains, Hélicase IFIH1 inductrice de l'interféron, Methyltransferases, Motifs d'acides aminés, Mutation, Mâle, Protéines de liaison à l'ARN, Protéines virales non structurales, Réplication virale, Souris, Souris de lignée BALB C, Souris de lignée C57BL, Virulence.
English descriptors
- KwdEn :
- Amino Acid Motifs, Animals, Carrier Proteins (genetics), Carrier Proteins (metabolism), DEAD-box RNA Helicases (genetics), DEAD-box RNA Helicases (metabolism), Female, Humans, Interferon-Induced Helicase, IFIH1, Male, Methyltransferases (chemistry), Methyltransferases (genetics), Methyltransferases (metabolism), Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mutation, RNA-Binding Proteins, SARS Virus (enzymology), SARS Virus (genetics), SARS Virus (pathogenicity), SARS Virus (physiology), Severe Acute Respiratory Syndrome (genetics), Severe Acute Respiratory Syndrome (metabolism), Severe Acute Respiratory Syndrome (virology), Viral Nonstructural Proteins (chemistry), Viral Nonstructural Proteins (genetics), Viral Nonstructural Proteins (metabolism), Virulence, Virus Replication.
- MESH :
- chemical , chemistry : Methyltransferases, Viral Nonstructural Proteins.
- chemical , genetics : Carrier Proteins, DEAD-box RNA Helicases, Methyltransferases, Viral Nonstructural Proteins.
- chemical , metabolism : Carrier Proteins, DEAD-box RNA Helicases, Methyltransferases, Viral Nonstructural Proteins.
- enzymology : SARS Virus.
- genetics : SARS Virus, Severe Acute Respiratory Syndrome.
- metabolism : Severe Acute Respiratory Syndrome.
- pathogenicity : SARS Virus.
- physiology : SARS Virus.
- virology : Severe Acute Respiratory Syndrome.
- Amino Acid Motifs, Animals, Female, Humans, Interferon-Induced Helicase, IFIH1, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mutation, RNA-Binding Proteins, Virulence, Virus Replication.
Abstract
The sudden emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and, more recently, Middle Eastern respiratory syndrome CoV (MERS-CoV) underscores the importance of understanding critical aspects of CoV infection and pathogenesis. Despite significant insights into CoV cross-species transmission, replication, and virus-host interactions, successful therapeutic options for CoVs do not yet exist. Recent identification of SARS-CoV NSP16 as a viral 2'-O-methyltransferase (2'-O-MTase) led to the possibility of utilizing this pathway to both attenuate SARS-CoV infection and develop novel therapeutic treatment options. Mutations were introduced into SARS-CoV NSP16 within the conserved KDKE motif and effectively attenuated the resulting SARS-CoV mutant viruses both in vitro and in vivo. While viruses lacking 2'-O-MTase activity had enhanced sensitivity to type I interferon (IFN), they were not completely restored in their absence in vivo. However, the absence of either MDA5 or IFIT1, IFN-responsive genes that recognize unmethylated 2'-O RNA, resulted in restored replication and virulence of the dNSP16 mutant virus. Finally, using the mutant as a live-attenuated vaccine showed significant promise for possible therapeutic development against SARS-CoV. Together, the data underscore the necessity of 2'-O-MTase activity for SARS-CoV pathogenesis and identify host immune pathways that mediate this attenuation. In addition, we describe novel treatment avenues that exploit this pathway and could potentially be used against a diverse range of viral pathogens that utilize 2'-O-MTase activity to subvert the immune system.
DOI: 10.1128/JVI.03571-13
PubMed: 24478444
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 001A70
- to stream PubMed, to step Curation: 001A70
- to stream PubMed, to step Checkpoint: 001990
- to stream Ncbi, to step Merge: 000C73
- to stream Ncbi, to step Curation: 000C73
- to stream Ncbi, to step Checkpoint: 000C73
- to stream Main, to step Merge: 001D55
- to stream Main, to step Curation: 001D40
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity.</title><author><name sortKey="Menachery, Vineet D" sort="Menachery, Vineet D" uniqKey="Menachery V" first="Vineet D" last="Menachery">Vineet D. Menachery</name><affiliation wicri:level="2"><nlm:affiliation>Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Yount, Boyd L" sort="Yount, Boyd L" uniqKey="Yount B" first="Boyd L" last="Yount">Boyd L. Yount</name></author><author><name sortKey="Josset, Laurence" sort="Josset, Laurence" uniqKey="Josset L" first="Laurence" last="Josset">Laurence Josset</name></author><author><name sortKey="Gralinski, Lisa E" sort="Gralinski, Lisa E" uniqKey="Gralinski L" first="Lisa E" last="Gralinski">Lisa E. Gralinski</name></author><author><name sortKey="Scobey, Trevor" sort="Scobey, Trevor" uniqKey="Scobey T" first="Trevor" last="Scobey">Trevor Scobey</name></author><author><name sortKey="Agnihothram, Sudhakar" sort="Agnihothram, Sudhakar" uniqKey="Agnihothram S" first="Sudhakar" last="Agnihothram">Sudhakar Agnihothram</name></author><author><name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G" last="Katze">Michael G. Katze</name></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S" last="Baric">Ralph S. Baric</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:24478444</idno><idno type="pmid">24478444</idno><idno type="doi">10.1128/JVI.03571-13</idno><idno type="wicri:Area/PubMed/Corpus">001A70</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001A70</idno><idno type="wicri:Area/PubMed/Curation">001A70</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001A70</idno><idno type="wicri:Area/PubMed/Checkpoint">001990</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001990</idno><idno type="wicri:Area/Ncbi/Merge">000C73</idno><idno type="wicri:Area/Ncbi/Curation">000C73</idno><idno type="wicri:Area/Ncbi/Checkpoint">000C73</idno><idno type="wicri:Area/Main/Merge">001D55</idno><idno type="wicri:Area/Main/Curation">001D40</idno><idno type="wicri:Area/Main/Exploration">001D40</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity.</title><author><name sortKey="Menachery, Vineet D" sort="Menachery, Vineet D" uniqKey="Menachery V" first="Vineet D" last="Menachery">Vineet D. Menachery</name><affiliation wicri:level="2"><nlm:affiliation>Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Yount, Boyd L" sort="Yount, Boyd L" uniqKey="Yount B" first="Boyd L" last="Yount">Boyd L. Yount</name></author><author><name sortKey="Josset, Laurence" sort="Josset, Laurence" uniqKey="Josset L" first="Laurence" last="Josset">Laurence Josset</name></author><author><name sortKey="Gralinski, Lisa E" sort="Gralinski, Lisa E" uniqKey="Gralinski L" first="Lisa E" last="Gralinski">Lisa E. Gralinski</name></author><author><name sortKey="Scobey, Trevor" sort="Scobey, Trevor" uniqKey="Scobey T" first="Trevor" last="Scobey">Trevor Scobey</name></author><author><name sortKey="Agnihothram, Sudhakar" sort="Agnihothram, Sudhakar" uniqKey="Agnihothram S" first="Sudhakar" last="Agnihothram">Sudhakar Agnihothram</name></author><author><name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G" last="Katze">Michael G. Katze</name></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S" last="Baric">Ralph S. Baric</name></author></analytic><series><title level="j">Journal of virology</title><idno type="eISSN">1098-5514</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 Motifs</term><term>Animals</term><term>Carrier Proteins (genetics)</term><term>Carrier Proteins (metabolism)</term><term>DEAD-box RNA Helicases (genetics)</term><term>DEAD-box RNA Helicases (metabolism)</term><term>Female</term><term>Humans</term><term>Interferon-Induced Helicase, IFIH1</term><term>Male</term><term>Methyltransferases (chemistry)</term><term>Methyltransferases (genetics)</term><term>Methyltransferases (metabolism)</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Mice, Inbred C57BL</term><term>Mutation</term><term>RNA-Binding Proteins</term><term>SARS Virus (enzymology)</term><term>SARS Virus (genetics)</term><term>SARS Virus (pathogenicity)</term><term>SARS Virus (physiology)</term><term>Severe Acute Respiratory Syndrome (genetics)</term><term>Severe Acute Respiratory Syndrome (metabolism)</term><term>Severe Acute Respiratory Syndrome (virology)</term><term>Viral Nonstructural Proteins (chemistry)</term><term>Viral Nonstructural Proteins (genetics)</term><term>Viral Nonstructural Proteins (metabolism)</term><term>Virulence</term><term>Virus Replication</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>DEAD-box RNA helicases (génétique)</term><term>DEAD-box RNA helicases (métabolisme)</term><term>Femelle</term><term>Humains</term><term>Hélicase IFIH1 inductrice de l'interféron</term><term>Methyltransferases ()</term><term>Methyltransferases (génétique)</term><term>Methyltransferases (métabolisme)</term><term>Motifs d'acides aminés</term><term>Mutation</term><term>Mâle</term><term>Protéines de liaison à l'ARN</term><term>Protéines de transport (génétique)</term><term>Protéines de transport (métabolisme)</term><term>Protéines virales non structurales ()</term><term>Protéines virales non structurales (génétique)</term><term>Protéines virales non structurales (métabolisme)</term><term>Réplication virale</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Souris de lignée C57BL</term><term>Syndrome respiratoire aigu sévère (génétique)</term><term>Syndrome respiratoire aigu sévère (métabolisme)</term><term>Syndrome respiratoire aigu sévère (virologie)</term><term>Virulence</term><term>Virus du SRAS (enzymologie)</term><term>Virus du SRAS (génétique)</term><term>Virus du SRAS (pathogénicité)</term><term>Virus du SRAS (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Methyltransferases</term><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Carrier Proteins</term><term>DEAD-box RNA Helicases</term><term>Methyltransferases</term><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Carrier Proteins</term><term>DEAD-box RNA Helicases</term><term>Methyltransferases</term><term>Viral Nonstructural Proteins</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="genetics" xml:lang="en"><term>SARS Virus</term><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>DEAD-box RNA helicases</term><term>Methyltransferases</term><term>Protéines de transport</term><term>Protéines virales non structurales</term><term>Syndrome respiratoire aigu sévère</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>DEAD-box RNA helicases</term><term>Methyltransferases</term><term>Protéines de transport</term><term>Protéines virales non structurales</term><term>Syndrome respiratoire aigu sévère</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>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>SARS Virus</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 Motifs</term><term>Animals</term><term>Female</term><term>Humans</term><term>Interferon-Induced Helicase, IFIH1</term><term>Male</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Mice, Inbred C57BL</term><term>Mutation</term><term>RNA-Binding Proteins</term><term>Virulence</term><term>Virus Replication</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Femelle</term><term>Humains</term><term>Hélicase IFIH1 inductrice de l'interféron</term><term>Methyltransferases</term><term>Motifs d'acides aminés</term><term>Mutation</term><term>Mâle</term><term>Protéines de liaison à l'ARN</term><term>Protéines virales non structurales</term><term>Réplication virale</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Souris de lignée C57BL</term><term>Virulence</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The sudden emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and, more recently, Middle Eastern respiratory syndrome CoV (MERS-CoV) underscores the importance of understanding critical aspects of CoV infection and pathogenesis. Despite significant insights into CoV cross-species transmission, replication, and virus-host interactions, successful therapeutic options for CoVs do not yet exist. Recent identification of SARS-CoV NSP16 as a viral 2'-O-methyltransferase (2'-O-MTase) led to the possibility of utilizing this pathway to both attenuate SARS-CoV infection and develop novel therapeutic treatment options. Mutations were introduced into SARS-CoV NSP16 within the conserved KDKE motif and effectively attenuated the resulting SARS-CoV mutant viruses both in vitro and in vivo. While viruses lacking 2'-O-MTase activity had enhanced sensitivity to type I interferon (IFN), they were not completely restored in their absence in vivo. However, the absence of either MDA5 or IFIT1, IFN-responsive genes that recognize unmethylated 2'-O RNA, resulted in restored replication and virulence of the dNSP16 mutant virus. Finally, using the mutant as a live-attenuated vaccine showed significant promise for possible therapeutic development against SARS-CoV. Together, the data underscore the necessity of 2'-O-MTase activity for SARS-CoV pathogenesis and identify host immune pathways that mediate this attenuation. In addition, we describe novel treatment avenues that exploit this pathway and could potentially be used against a diverse range of viral pathogens that utilize 2'-O-MTase activity to subvert the immune system.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Caroline du Nord</li></region></list><tree><noCountry><name sortKey="Agnihothram, Sudhakar" sort="Agnihothram, Sudhakar" uniqKey="Agnihothram S" first="Sudhakar" last="Agnihothram">Sudhakar Agnihothram</name><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S" last="Baric">Ralph S. Baric</name><name sortKey="Gralinski, Lisa E" sort="Gralinski, Lisa E" uniqKey="Gralinski L" first="Lisa E" last="Gralinski">Lisa E. Gralinski</name><name sortKey="Josset, Laurence" sort="Josset, Laurence" uniqKey="Josset L" first="Laurence" last="Josset">Laurence Josset</name><name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G" last="Katze">Michael G. Katze</name><name sortKey="Scobey, Trevor" sort="Scobey, Trevor" uniqKey="Scobey T" first="Trevor" last="Scobey">Trevor Scobey</name><name sortKey="Yount, Boyd L" sort="Yount, Boyd L" uniqKey="Yount B" first="Boyd L" last="Yount">Boyd L. Yount</name></noCountry><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Menachery, Vineet D" sort="Menachery, Vineet D" uniqKey="Menachery V" first="Vineet D" last="Menachery">Vineet D. Menachery</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/MersV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001D40 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 001D40 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= MersV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:24478444
|texte= Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:24478444" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a MersV1
| This area was generated with Dilib version V0.6.33. |  |