MicroRNA-30c Modulates Type I IFN Responses To Facilitate Porcine Reproductive and Respiratory Syndrome Virus Infection by Targeting JAK1

Zhang, Qiong; Huang, Chen; Yang, Qian; Gao, Li; Liu, Hsiao‐Ching; Tang, Jun; Feng, Wen-hai

doi:10.4049/jimmunol.1502006

Cited by 82 publications

(49 citation statements)

References 48 publications

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“…FOS (FBJ murine osteosarcoma viral oncogene homolog), as a cellular immediate-early gene was markedly induced before expressions of the Epstein-Barr Virus (EBV) transactivator genes were activated [35], which was similar in the process of IBDV infection. Likewise, host immune-related genes, such as VCAM1, NFKB1 and TLR2/3, were also elevated at the early stage in the infection group, which were consistent with many previous reports [36–38]. …”

Section: Discussionsupporting

confidence: 92%

Transcription profiles of the responses of chicken bursae of Fabricius to IBDV in different timing phases

Wang

Zhang

et al. 2017

Virol J

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BackgroundInfectious bursal disease virus (IBDV) infection causes immunosuppression in chickens and increases their susceptibility to secondary infections. To explore the interaction between host and IBDV, RNA-Seq was applied to analyse the transcriptional profiles of the responses of chickens’ bursas of Fabricius in the early stage of IBDV infection.ResultsThe results displayed that a total of 15546 genes were identified in the chicken bursa libraries. Among the annotated genes, there were 2006 and 4668 differentially expressed genes in the infection group compared with the mock group on day 1 and day 3 post inoculation (1 and 3 dpi), respectively. Moreover, there were 676 common up-regulated and 83 common down-regulated genes in the bursae taken from the chickens infected with IBDV on both 1 and 3 dpi. Meanwhile, there were also some characteristic differentially expressed genes on 1 and 3 dpi. On day 1 after inoculation with IBDV, host responses mainly displayed immune response processes, while metabolic pathways played an important role on day three post infection. Six genes were confirmed by quantitative reverse transcription-PCR.ConclusionsIn conclusion, the differential gene expression profile demonstrated with RNA-Seq might offer a better understanding of the molecular interactions between host and IBDV during the early stage of infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-017-0757-x) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Transcription profiles of the responses of chicken bursae of Fabricius to IBDV in different timing phases

Wang

Zhang

et al. 2017

Virol J

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“…Inhibition of NF-B activation by pyrrolidine dithiocarbamate leads to a significant decrease in the levels of heparanase (20), indicating that NF-B might be an important regulator of heparanase. A number of reports have also demonstrated that PRRSV infection can activate the NF-B signaling pathway by IB␣ degradation and nuclear translocation of p65, a key subunit of NF-B (21,22). We therefore investigated the possible connection between NF-B and heparanase after PRRSV infection.…”

Section: Resultsmentioning

confidence: 96%

Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release

Guo

Zhu

Guo

et al. 2017

J Virol

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Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause substantial economic losses to the pig industry worldwide. Heparan sulfate (HS) is used by PRRSV for initial attachment to target cells. However, the role of HS in the late phase of PRRSV infection and the mechanism of virus release from host cells remain largely unknown. In this study, we showed that PRRSV infection caused a decrease in HS expression and upregulated heparanase, the only known enzyme capable of degrading HS. We subsequently demonstrated that the NF-B signaling pathway and cathepsin L protease were involved in regulation of PRRSV infectioninduced heparanase. In addition, we found that ablation of heparanase expression using small interfering RNA duplexes increased cell surface expression of HS and suppressed PRRSV replication and release, whereas overexpression of heparanase reduced HS surface expression and enhanced PRRSV replication and release. These data suggest that PRRSV activates NF-B and cathepsin L to upregulate and process heparanase, and then the active heparanase cleaves HS, resulting in viral release. Our findings provide new insight into the molecular mechanism of PRRSV egress from host cells, which might help us to further understand PRRSV pathogenesis.IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) causes great economic losses each year to the pig industry worldwide. The molecular mechanism of PRRSV release from host cells largely remains a mystery. In this study, we demonstrate that PRRSV activates NF-B and cathepsin L to upregulate and process heparanase, and then the active heparanase is released to the extracellular space and exerts enzymatic activity to cleave heparan sulfate, resulting in viral release. Our findings provide new insight into the molecular mechanism of PRRSV egress from host cells, which might help us to further understand PRRSV pathogenesis.KEYWORDS PRRSV, heparan sulfate, heparanase, viral release, porcine reproductive and respiratory syndrome virus P orcine reproductive and respiratory syndrome (PRRS) has become one of the most important diseases of intensive pig production worldwide since its emergence in the late 1980s (1, 2). This disease is characterized by respiratory disease, weight loss, and poor growth performance, as well as by late-term abortions (3). The causative agent, PRRS virus (PRRSV), is a small, enveloped, positive-sense, single-stranded RNA virus of the genus Arterivirus, in the family Arteriviridae within the order Nidovirales (4, 5). The PRRSV genome is approximately 15 kb in length and consists of at least 12 overlapping open reading frames (6, 7). Due to the genetic and antigenic differences, PRRSV can be divided into European genotype 1 and North American genotype 2, with Lelystad and VR-2332 as prototypical strains, respectively, which share about 60% nucleotide sequence identity (8). In 2006, highly pathogenic PRRSV (HP-PRRSV)

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“…TGEV infection downregulates miR-30a-5p expression. The host miR-30 family (five members, consisting of miR30a to miR30e) plays important roles in cancers and viral infections (30,34,36,37). We recently reported that miR-30a-5p, a member of the miR-30 family, is downregulated and that is expression is inversely correlated with the levels of ER stress in renal cancer, indicating that ER stress might inhibit miR-30a-5p expression (34).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, a mutant vector was constructed to eliminate possible recognition by replacing five seed nucleotides (in which the underlined nucleotides in the sequence UGUUUAC were changed, resulting in the sequence UAGGGUC) as previously described (Fig. 5A) (30). Compared with the NC mimic treatment, overexpression of miR-30a-5p in ST cells decreased the activity of the luciferase reporter containing the SOCS1 or SOCS3 wild-type target sequence but not that of the luciferase reporter containing the mutant target site of SOCS1 or SOCS3.…”

Section: Resultsmentioning

confidence: 99%

The Coronavirus Transmissible Gastroenteritis Virus Evades the Type I Interferon Response through IRE1α-Mediated Manipulation of the MicroRNA miR-30a-5p/SOCS1/3 Axis

Wang

Xue

et al. 2018

J Virol

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In host innate immunity, type I interferons (IFN-I) are major antiviral molecules, and coronaviruses have evolved diverse strategies to counter the IFN-I response during infection. Transmissible gastroenteritis virus (TGEV), a member of the family, induces endoplasmic reticulum (ER) stress and significant IFN-I production after infection. However, how TGEV evades the IFN-I antiviral response despite the marked induction of endogenous IFN-I has remained unclear. Inositol-requiring enzyme 1 α (IRE1α), a highly conserved ER stress sensor with both kinase and RNase activities, is involved in the IFN response. In this study, IRE1α facilitated TGEV replication via downmodulating the host microRNA (miR) miR-30a-5p abundance. miR-30a-5p normally enhances IFN-I antiviral activity by directly targeting the negative regulators of Janus family kinase (JAK)-signal transducer and activator of transcription (STAT), the suppressor of cytokine signaling protein 1 (SOCS1), and SOCS3. Furthermore, TGEV infection increased SOCS1 and SOCS3 expression, which dampened the IFN-I antiviral response and facilitated TGEV replication. Importantly, compared with mock infection, TGEV infection resulted in decreased miR-30a-5p levels and significantly elevated SOCS1 and SOCS3 expression in the piglet ileum. Taken together, our data reveal a new strategy used by TGEV to escape the IFN-I response by engaging the IRE1α-miR-30a-5p/SOCS1/3 axis, thus improving our understanding of how TGEV escapes host innate immune defenses. Type I interferons (IFN-I) play essential roles in restricting viral infections. Coronavirus infection induces ER stress and the interferon response, which reflects different adaptive cellular processes. An understanding of how coronavirus-elicited ER stress is actively involved in viral replication and manipulates the host IFN-I response has remained elusive. Here, TGEV inhibited host miR-30a-5p via the ER stress sensor IRE1α, which led to the increased expression of negative regulators of JAK-STAT signaling cascades, namely, SOCS1 and SOCS3. Increased SOCS1 or SOCS3 expression impaired the IFN-I antiviral response, promoting TGEV replication. These findings enhance our understanding of the strategies used by coronaviruses to antagonize IFN-I innate immunity via IRE1α-mediated manipulation of the miR-30a-5p/SOCS axis, highlighting the crucial role of IRE1α in innate antiviral resistance and the potential of IRE1α as a novel target against coronavirus infection.

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MicroRNA-30c Modulates Type I IFN Responses To Facilitate Porcine Reproductive and Respiratory Syndrome Virus Infection by Targeting JAK1

Cited by 82 publications

References 48 publications

Transcription profiles of the responses of chicken bursae of Fabricius to IBDV in different timing phases

Transcription profiles of the responses of chicken bursae of Fabricius to IBDV in different timing phases

Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release

The Coronavirus Transmissible Gastroenteritis Virus Evades the Type I Interferon Response through IRE1α-Mediated Manipulation of the MicroRNA miR-30a-5p/SOCS1/3 Axis

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