scholarly journals Porcine Reproductive and Respiratory Syndrome Virus Nonstructural Protein 1β Modulates Host Innate Immune Response by Antagonizing IRF3 Activation

2009 ◽  
Vol 84 (3) ◽  
pp. 1574-1584 ◽  
Author(s):  
Lalit K. Beura ◽  
Saumendra N. Sarkar ◽  
Byungjoon Kwon ◽  
Sakthivel Subramaniam ◽  
Clinton Jones ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Nuclear Translocation ◽  
Sendai Virus ◽  
Nonstructural Protein ◽  
Adaptive Immune Response ◽  
Inhibitory Effect ◽  
Innate Immune ◽  
Respiratory Syndrome Virus ◽  
Host Innate Immune Response

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.

Nonstructural protein p39 of feline calicivirus suppresses host innate immune response by preventing IRF-3 activation

2016 ◽  
Vol 185 ◽  
pp. 62-67 ◽  
Author(s):  
Yo Yumiketa ◽  
Takanori Narita ◽  
Yosuke Inoue ◽  
Go Sato ◽  
Wataru Kamitani ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Nonstructural Protein ◽  
Innate Immune ◽  
Feline Calicivirus ◽  
Host Innate Immune Response

scholarly journals Japanese Encephalitis Virus NS5 Inhibits Type I Interferon (IFN) Production by Blocking the Nuclear Translocation of IFN Regulatory Factor 3 and NF-κB

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Jing Ye ◽  
Zheng Chen ◽  
Yunchuan Li ◽  
Zikai Zhao ◽  
Wen He ◽  
...  
Keyword(s):  
Immune Response ◽  
Japanese Encephalitis Virus ◽  
Innate Immune Response ◽  
Nuclear Translocation ◽  
Type I Interferon ◽  
Transport Proteins ◽  
Innate Immune ◽  
Type I ◽  
Regulatory Factor ◽  
Host Innate Immune Response

ABSTRACT The type I interferon (IFN) response is part of the first-line defense against viral infection. To initiate replication, viruses have developed powerful evasion strategies to counteract host IFN responses. In the present study, we found that the Japanese encephalitis virus (JEV) NS5 protein could inhibit double-stranded RNA (dsRNA)-induced IFN-β expression in a dose-dependent manner. Our data further demonstrated that JEV NS5 suppressed the activation of the IFN transcriptional factors IFN regulatory factor 3 (IRF3) and NF-κB. However, there was no defect in the phosphorylation of IRF3 and degradation of IκB, an upstream inhibitor of NF-κB, upon NS5 expression, indicating a direct inhibition of the nuclear localization of IRF3 and NF-κB by NS5. Mechanistically, NS5 was shown to interact with the nuclear transport proteins KPNA2, KPNA3, and KPNA4, which competitively blocked the interaction of KPNA3 and KPNA4 with their cargo molecules, IRF3 and p65, a subunit of NF-κB, and thus inhibited the nuclear translocation of IRF3 and NF-κB. Furthermore, overexpression of KPNA3 and KPNA4 restored the activity of IRF3 and NF-κB and increased the production of IFN-β in NS5-expressing or JEV-infected cells. Additionally, an upregulated replication level of JEV was shown upon KPNA3 or KPNA4 overexpression. These results suggest that JEV NS5 inhibits the induction of type I IFN by targeting KPNA3 and KPNA4. IMPORTANCE JEV is the major cause of viral encephalitis in South and Southeast Asia, with high mortality. However, the molecular mechanisms contributing to the severe pathogenesis are poorly understood. The ability of JEV to counteract the host innate immune response is potentially one of the mechanisms responsible for JEV virulence. Here we demonstrate the ability of JEV NS5 to interfere with the dsRNA-induced nuclear translocation of IRF3 and NF-κB by competitively inhibiting the interaction of IRF3 and NF-κB with nuclear transport proteins. Via this mechanism, JEV NS5 suppresses the induction of type I IFN and the antiviral response in host cells. These findings reveal a novel strategy for JEV to escape the host innate immune response and provide new insights into the pathogenesis of JEV.

scholarly journals Genetic basis of host innate immune response in mastitis caused by Staphylococcus aureus

2012 ◽  
Vol 4 ◽  
pp. 405-409 ◽  
Author(s):  
Adrianna Pawlik ◽  
Grażyna Sender ◽  
Rafał Starzyński ◽  
Agnieszka Korwin-Kossakowska
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Response ◽  
Innate Immune Response ◽  
Genetic Basis ◽  
Innate Immune ◽  
Host Innate Immune Response

scholarly journals Mammalian Orthoreovirus Factories Modulate Stress Granule Protein Localization by Interaction with G3BP1

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Promisree Choudhury ◽  
Luke D. Bussiere ◽  
Cathy L. Miller
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Innate Immune Response ◽  
Nonstructural Protein ◽  
Innate Immune ◽  
Common Mechanism ◽  
Effector Protein ◽  
Associated Proteins ◽  
Mammalian Orthoreovirus ◽  
Late Stages

ABSTRACT Mammalian orthoreovirus (MRV) infection induces phosphorylation of translation initiation factor eIF2α, which promotes the formation of discrete cytoplasmic inclusions, termed stress granules (SGs). SGs are emerging as a component of the innate immune response to virus infection, and modulation of SG assembly is a common mechanism employed by viruses to counter this antiviral response. We previously showed that MRV infection induces SGs early and then interferes with SG formation as infection proceeds. In this work, we found that SG-associated proteins localized to the periphery of virus-encoded cytoplasmic structures, termed virus factories (VFs), where viral transcription, translation, and replication occur. The localization of SG proteins to VFs was dependent on polysome dissociation and occurred via association of the SG effector protein, Ras-GAP SH3-binding protein 1 (G3BP1), with the MRV nonstructural protein σNS, which localizes to VFs via association with VF nucleating protein, μNS. Deletion analysis of the σNS RNA binding domain and G3BP1 RNA (RRM) and ribosomal (RGG) binding domains showed that σNS association and VF localization phenotypes of G3BP1 do not occur solely through RNA or ribosomal binding but require both the RRM and RGG domains of G3BP1 for maximal viral-factory-like structure (VFL) localization and σNS association. Coexpression of σNS and μNS resulted in disruption of normal SG puncta, and in cells lacking G3BP1, MRV replication was enhanced in a manner correlating with strain-dependent induction of host translation shutoff. These results suggest that σNS association with G3BP1 and relocalization of G3BP1 to the VF periphery play roles in SG disruption to facilitate MRV replication in the host translational shutoff environment. IMPORTANCE SGs and SG effector proteins have emerged as important, yet poorly understood, players in the host's innate immune response to virus infection. MRV infection induces SGs early during infection that are dispersed and/or prevented from forming during late stages of infection despite continued activation of the eIF2α signaling pathway. Cellular and viral components involved in disruption of SGs during late stages of MRV infection remain to be elucidated. This work provides evidence that MRV disruption of SGs may be facilitated by association of the MRV nonstructural protein σNS with the major SG effector protein G3BP1 and subsequent localization of G3BP1 and other SG-associated proteins around the peripheries of virus-encoded factories, interrupting the normal formation of SGs. Our findings also reveal the importance of G3BP1 as an inhibitor of MRV replication during infection for the first time.

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