Proteasome Inhibition In Vivo Promotes Survival in a Lethal Murine Model of Severe Acute Respiratory Syndrome
Identifieur interne : 002927 ( Main/Exploration ); précédent : 002926; suivant : 002928Proteasome Inhibition In Vivo Promotes Survival in a Lethal Murine Model of Severe Acute Respiratory Syndrome
Auteurs : Xue-Zhong Ma [Canada] ; Agata Bartczak [Canada] ; JIANHUA ZHANG [Canada] ; Ramzi Khattar [Canada] ; LIMIN CHEN [Canada] ; MING FENG LIU [Canada] ; Aled Edwards [Canada] ; Gary Levy [Canada] ; Ian D. Mcgilvra [Canada]Source :
- Journal of virology [ 0022-538X ] ; 2010.
Descripteurs français
- Pascal (Inist)
English descriptors
Abstract
Ubiquitination is a critical regulator of the host immune response to viral infection, and many viruses, including coronaviruses, encode proteins that target the ubiquitination system. To explore the link between coronavirus infection and the ubiquitin system, we asked whether protein degradation by the 26S proteasome plays a role in severe coronavirus infections using a murine model of SARS-like pneumonitis induced by murine hepatitis virus strain 1 (MHV-1). In vitro, the pretreatment of peritoneal macrophages with inhibitors of the proteasome (pyrrolidine dithiocarbamate [PDTC], MG132, and PS-341) markedly inhibited MHV-1 replication at an early step in its replication cycle, as evidenced by inhibition of viral RNA production. Proteasome inhibition also blocked viral cytotoxicity in macrophages, as well as the induction of inflammatory mediators such as IP-10, gamma interferon (IFN-γ), and monocyte chemoattractant protein 1 (MCP-1). In vivo, intranasal inoculation of MHV-1 results in a lethal pneumonitis in A/J mice. Treatment ofA/J mice with the proteasome inhibitor PDTC, MG132, or PS-341 led to 40% survival (P < 0.01), with a concomitant improvement of lung histology, reduced pulmonary viral replication, decreased pulmonary STAT phosphorylation, and reduced pulmonary inflammatory cytokine expression. These data demonstrate that inhibition of the cellular proteasome attenuates pneumonitis and cytokine gene expression in vivo by reducing MHV-1 replication and the resulting inflammatory response. The results further suggest that targeting the proteasome may be an effective new treatment for severe coronavirus infections.
Affiliations:
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Research Institute, University Health Network</s1><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</wicri:noRegion></affiliation></author><author><name sortKey="Bartczak, Agata" sort="Bartczak, Agata" uniqKey="Bartczak A" first="Agata" last="Bartczak">Agata Bartczak</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</s1><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</wicri:noRegion></affiliation></author><author><name sortKey="Jianhua Zhang" sort="Jianhua Zhang" uniqKey="Jianhua Zhang" last="Jianhua Zhang">JIANHUA ZHANG</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</s1><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</wicri:noRegion></affiliation></author><author><name sortKey="Khattar, Ramzi" sort="Khattar, Ramzi" uniqKey="Khattar R" first="Ramzi" last="Khattar">Ramzi Khattar</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</s1><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</wicri:noRegion></affiliation></author><author><name sortKey="Limin Chen" sort="Limin Chen" uniqKey="Limin Chen" last="Limin Chen">LIMIN CHEN</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Best Department of Medical Research, University of Toronto</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université de Toronto</orgName></affiliation></author><author><name sortKey="Ming Feng Liu" sort="Ming Feng Liu" uniqKey="Ming Feng Liu" last="Ming Feng Liu">MING FENG LIU</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</s1><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</wicri:noRegion></affiliation></author><author><name sortKey="Edwards, Aled" sort="Edwards, Aled" uniqKey="Edwards A" first="Aled" last="Edwards">Aled Edwards</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Best Department of Medical Research, University of Toronto</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université de Toronto</orgName></affiliation></author><author><name sortKey="Levy, Gary" sort="Levy, Gary" uniqKey="Levy G" first="Gary" last="Levy">Gary Levy</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</s1><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</wicri:noRegion></affiliation><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Medicine, University of Toronto</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>8 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université de Toronto</orgName></affiliation></author><author><name sortKey="Mcgilvra, Ian D" sort="Mcgilvra, Ian D" uniqKey="Mcgilvra I" first="Ian D." last="Mcgilvra">Ian D. Mcgilvra</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</s1><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Multi-Organ Transplant Program, Toronto General Research Institute, University Health Network</wicri:noRegion></affiliation><affiliation wicri:level="4"><inist:fA14 i1="04"><s1>Department of Surgery, University of Toronto</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université de Toronto</orgName></affiliation></author></analytic><series><title level="j" type="main">Journal of virology</title><title level="j" type="abbreviated">J. virol.</title><idno type="ISSN">0022-538X</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of virology</title><title level="j" type="abbreviated">J. virol.</title><idno type="ISSN">0022-538X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal model</term><term>Multicatalytic endopeptidase complex</term><term>Severe acute respiratory syndrome</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Multicatalytic endopeptidase complex</term><term>Modèle animal</term><term>Syndrome respiratoire aigu sévère</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Ubiquitination is a critical regulator of the host immune response to viral infection, and many viruses, including coronaviruses, encode proteins that target the ubiquitination system. To explore the link between coronavirus infection and the ubiquitin system, we asked whether protein degradation by the 26S proteasome plays a role in severe coronavirus infections using a murine model of SARS-like pneumonitis induced by murine hepatitis virus strain 1 (MHV-1). In vitro, the pretreatment of peritoneal macrophages with inhibitors of the proteasome (pyrrolidine dithiocarbamate [PDTC], MG132, and PS-341) markedly inhibited MHV-1 replication at an early step in its replication cycle, as evidenced by inhibition of viral RNA production. Proteasome inhibition also blocked viral cytotoxicity in macrophages, as well as the induction of inflammatory mediators such as IP-10, gamma interferon (IFN-γ), and monocyte chemoattractant protein 1 (MCP-1). In vivo, intranasal inoculation of MHV-1 results in a lethal pneumonitis in A/J mice. Treatment ofA/J mice with the proteasome inhibitor PDTC, MG132, or PS-341 led to 40% survival (P < 0.01), with a concomitant improvement of lung histology, reduced pulmonary viral replication, decreased pulmonary STAT phosphorylation, and reduced pulmonary inflammatory cytokine expression. These data demonstrate that inhibition of the cellular proteasome attenuates pneumonitis and cytokine gene expression in vivo by reducing MHV-1 replication and the resulting inflammatory response. The results further suggest that targeting the proteasome may be an effective new treatment for severe coronavirus infections.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><country name="Canada"><noRegion><name sortKey="Ma, Xue Zhong" sort="Ma, Xue Zhong" uniqKey="Ma X" first="Xue-Zhong" last="Ma">Xue-Zhong Ma</name></noRegion><name sortKey="Bartczak, Agata" sort="Bartczak, Agata" uniqKey="Bartczak A" first="Agata" last="Bartczak">Agata Bartczak</name><name sortKey="Edwards, Aled" sort="Edwards, Aled" uniqKey="Edwards A" first="Aled" last="Edwards">Aled Edwards</name><name sortKey="Jianhua Zhang" sort="Jianhua Zhang" uniqKey="Jianhua Zhang" last="Jianhua Zhang">JIANHUA ZHANG</name><name sortKey="Khattar, Ramzi" sort="Khattar, Ramzi" uniqKey="Khattar R" first="Ramzi" last="Khattar">Ramzi Khattar</name><name sortKey="Levy, Gary" sort="Levy, Gary" uniqKey="Levy G" first="Gary" last="Levy">Gary Levy</name><name sortKey="Levy, Gary" sort="Levy, Gary" uniqKey="Levy G" first="Gary" last="Levy">Gary Levy</name><name sortKey="Limin Chen" sort="Limin Chen" uniqKey="Limin Chen" last="Limin Chen">LIMIN CHEN</name><name sortKey="Mcgilvra, Ian D" sort="Mcgilvra, Ian D" uniqKey="Mcgilvra I" first="Ian D." last="Mcgilvra">Ian D. Mcgilvra</name><name sortKey="Mcgilvra, Ian D" sort="Mcgilvra, Ian D" uniqKey="Mcgilvra I" first="Ian D." last="Mcgilvra">Ian D. Mcgilvra</name><name sortKey="Ming Feng Liu" sort="Ming Feng Liu" uniqKey="Ming Feng Liu" last="Ming Feng Liu">MING FENG LIU</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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