Porcine Reproductive and Respiratory Syndrome Virus Nonstructural Protein 1β Modulates Host Innate Immune Response by Antagonizing IRF3 Activation▿
Identifieur interne : 000618 ( Pmc/Checkpoint ); précédent : 000617; suivant : 000619Porcine Reproductive and Respiratory Syndrome Virus Nonstructural Protein 1β Modulates Host Innate Immune Response by Antagonizing IRF3 Activation▿
Auteurs : Lalit K. Beura ; Saumendra N. Sarkar ; Byungjoon Kwon ; Sakthivel Subramaniam ; Clinton Jones ; Asit K. Pattnaik ; Fernando A. OsorioSource :
- Journal of Virology [ 0022-538X ] ; 2009.
Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) infection of swine leads to a serious disease characterized by a delayed and defective adaptive immune response. It is hypothesized that a suboptimal innate immune response is responsible for the disease pathogenesis. In the study presented here we tested this hypothesis and identified several nonstructural proteins (NSPs) with innate immune evasion properties encoded by the PRRS viral genome. Four of the total ten PRRSV NSPs tested were found to have strong to moderate inhibitory effects on beta interferon (IFN-β) promoter activation. The strongest inhibitory effect was exhibited by NSP1 followed by, NSP2, NSP11, and NSP4. We focused on NSP1α and NSP1β (self-cleavage products of NSP1 during virus infection) and NSP11, three NSPs with strong inhibitory activity. All of three proteins, when expressed stably in cell lines, strongly inhibited double-stranded RNA (dsRNA) signaling pathways. NSP1β was found to inhibit both IFN regulatory factor 3 (IRF3)- and NF-κB-dependent gene induction by dsRNA and Sendai virus. Mechanistically, the dsRNA-induced phosphorylation and nuclear translocation of IRF3 were strongly inhibited by NSP1β. Moreover, when tested in a porcine myelomonocytic cell line, NSP1β inhibited Sendai virus-mediated activation of porcine IFN-β promoter activity. We propose that this NSP1β-mediated subversion of the host innate immune response plays an important role in PRRSV pathogenesis.
Url:
DOI: 10.1128/JVI.01326-09
PubMed: 19923190
PubMed Central: 2812326
Affiliations:
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<series><title level="j">Journal of Virology</title>
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<front><div type="abstract" xml:lang="en"><p>Porcine reproductive and respiratory syndrome virus (PRRSV) infection of swine leads to a serious disease characterized by a delayed and defective adaptive immune response. It is hypothesized that a suboptimal innate immune response is responsible for the disease pathogenesis. In the study presented here we tested this hypothesis and identified several nonstructural proteins (NSPs) with innate immune evasion properties encoded by the PRRS viral genome. Four of the total ten PRRSV NSPs tested were found to have strong to moderate inhibitory effects on beta interferon (IFN-β) promoter activation. The strongest inhibitory effect was exhibited by NSP1 followed by, NSP2, NSP11, and NSP4. We focused on NSP1α and NSP1β (self-cleavage products of NSP1 during virus infection) and NSP11, three NSPs with strong inhibitory activity. All of three proteins, when expressed stably in cell lines, strongly inhibited double-stranded RNA (dsRNA) signaling pathways. NSP1β was found to inhibit both IFN regulatory factor 3 (IRF3)- and NF-κB-dependent gene induction by dsRNA and Sendai virus. Mechanistically, the dsRNA-induced phosphorylation and nuclear translocation of IRF3 were strongly inhibited by NSP1β. Moreover, when tested in a porcine myelomonocytic cell line, NSP1β inhibited Sendai virus-mediated activation of porcine IFN-β promoter activity. We propose that this NSP1β-mediated subversion of the host innate immune response plays an important role in PRRSV pathogenesis.</p>
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<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id>
<journal-id journal-id-type="publisher-id">jvirol</journal-id>
<journal-title-group><journal-title>Journal of Virology</journal-title>
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<issn pub-type="ppub">0022-538X</issn>
<issn pub-type="epub">1098-5514</issn>
<publisher><publisher-name>American Society for Microbiology (ASM)</publisher-name>
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<article-id pub-id-type="publisher-id">1326-09</article-id>
<article-id pub-id-type="doi">10.1128/JVI.01326-09</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Cellular Response to Infection</subject>
</subj-group>
</article-categories>
<title-group><article-title>Porcine Reproductive and Respiratory Syndrome Virus Nonstructural Protein 1β Modulates Host Innate Immune Response by Antagonizing IRF3 Activation<xref ref-type="fn" rid="fn1">▿</xref>
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<contrib-group><contrib contrib-type="author"><name><surname>Beura</surname>
<given-names>Lalit K.</given-names>
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<xref ref-type="aff" rid="aff1">1</xref>
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<contrib contrib-type="author"><name><surname>Sarkar</surname>
<given-names>Saumendra N.</given-names>
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<xref ref-type="aff" rid="aff1">2</xref>
<xref ref-type="corresp" rid="cor1">*</xref>
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<contrib contrib-type="author"><name><surname>Kwon</surname>
<given-names>Byungjoon</given-names>
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<contrib contrib-type="author"><name><surname>Subramaniam</surname>
<given-names>Sakthivel</given-names>
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<contrib contrib-type="author"><name><surname>Jones</surname>
<given-names>Clinton</given-names>
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<contrib contrib-type="author"><name><surname>Pattnaik</surname>
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<contrib contrib-type="author"><name><surname>Osorio</surname>
<given-names>Fernando A.</given-names>
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<aff id="aff1">Nebraska Center for Virology and School of Veterinary and Biomedical Sciences, University of Nebraska, Lincoln, Nebraska 68583,<label>1</label>
Molecular Virology Program, University of Pittsburgh Cancer Institute and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213<label>2</label>
</aff>
<author-notes><corresp id="cor1"><label>*</label>
Corresponding authors. Mailing address for F. A. Osorio: 111 MOLR Nebraska Center for Virology, UNL East Campus, Lincoln, NE 68583-0900. Phone: (402) 472-7809. Fax: (402) 472-3323. E-mail: <email>fosorio@unl.edu</email>
. Mailing address for S. N. Sarkar: University of Pittsburgh Cancer Institute HCC 1.8, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: (412) 623-7720. Fax: (412) 623-7715. E-mail: <email>saumen@pitt.edu</email>
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<pub-date pub-type="ppub"><month>2</month>
<year>2010</year>
</pub-date>
<pub-date pub-type="epub"><day>18</day>
<month>11</month>
<year>2009</year>
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<volume>84</volume>
<issue>3</issue>
<fpage>1574</fpage>
<lpage>1584</lpage>
<history><date date-type="received"><day>27</day>
<month>6</month>
<year>2009</year>
</date>
<date date-type="accepted"><day>10</day>
<month>11</month>
<year>2009</year>
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<permissions><copyright-statement>Copyright © 2010, American Society for Microbiology</copyright-statement>
<copyright-year>2010</copyright-year>
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<abstract><p>Porcine reproductive and respiratory syndrome virus (PRRSV) infection of swine leads to a serious disease characterized by a delayed and defective adaptive immune response. It is hypothesized that a suboptimal innate immune response is responsible for the disease pathogenesis. In the study presented here we tested this hypothesis and identified several nonstructural proteins (NSPs) with innate immune evasion properties encoded by the PRRS viral genome. Four of the total ten PRRSV NSPs tested were found to have strong to moderate inhibitory effects on beta interferon (IFN-β) promoter activation. The strongest inhibitory effect was exhibited by NSP1 followed by, NSP2, NSP11, and NSP4. We focused on NSP1α and NSP1β (self-cleavage products of NSP1 during virus infection) and NSP11, three NSPs with strong inhibitory activity. All of three proteins, when expressed stably in cell lines, strongly inhibited double-stranded RNA (dsRNA) signaling pathways. NSP1β was found to inhibit both IFN regulatory factor 3 (IRF3)- and NF-κB-dependent gene induction by dsRNA and Sendai virus. Mechanistically, the dsRNA-induced phosphorylation and nuclear translocation of IRF3 were strongly inhibited by NSP1β. Moreover, when tested in a porcine myelomonocytic cell line, NSP1β inhibited Sendai virus-mediated activation of porcine IFN-β promoter activity. We propose that this NSP1β-mediated subversion of the host innate immune response plays an important role in PRRSV pathogenesis.</p>
</abstract>
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<tree><noCountry><name sortKey="Beura, Lalit K" sort="Beura, Lalit K" uniqKey="Beura L" first="Lalit K." last="Beura">Lalit K. Beura</name>
<name sortKey="Jones, Clinton" sort="Jones, Clinton" uniqKey="Jones C" first="Clinton" last="Jones">Clinton Jones</name>
<name sortKey="Kwon, Byungjoon" sort="Kwon, Byungjoon" uniqKey="Kwon B" first="Byungjoon" last="Kwon">Byungjoon Kwon</name>
<name sortKey="Osorio, Fernando A" sort="Osorio, Fernando A" uniqKey="Osorio F" first="Fernando A." last="Osorio">Fernando A. Osorio</name>
<name sortKey="Pattnaik, Asit K" sort="Pattnaik, Asit K" uniqKey="Pattnaik A" first="Asit K." last="Pattnaik">Asit K. Pattnaik</name>
<name sortKey="Sarkar, Saumendra N" sort="Sarkar, Saumendra N" uniqKey="Sarkar S" first="Saumendra N." last="Sarkar">Saumendra N. Sarkar</name>
<name sortKey="Subramaniam, Sakthivel" sort="Subramaniam, Sakthivel" uniqKey="Subramaniam S" first="Sakthivel" last="Subramaniam">Sakthivel Subramaniam</name>
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