MicroRNA miR-24-3p Promotes Porcine Reproductive and Respiratory Syndrome Virus Replication through Suppression of Heme Oxygenase-1 Expression

Xiao, Shuqi; Wang, Xue; Ni, Huaibao; Li, Na; Zhang, Angke; Liu, Hongliang; Pu, Fengxing; Xu, Liang; Gao, Jiming; Zhao, Qin; Yang, Mei; Wang, Chengbao; Sun, Yani; Du, Taofeng; Xu, Xingang; Zhang, Gaiping; Hiscox, Julian A.; Goodfellow, Ian

doi:10.1128/jvi.02810-14

Cited by 75 publications

(38 citation statements)

References 52 publications

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“…160 A number of miRs may regulate the expression of Nrf2, which may result in the altered regulation of HO-1. 160–163 Several miRs identified in direct HO-1 translational regulation include miR-24 164–166 miR-200c, 162 miR-204/miR-211, 167 miR-155, 168 miR-378, 169 miR-377, 170 and miR-217. 170 Additional indirect mechanisms for miR-dependent regulation of HO-1 have been proposed.…”

Section: Regulation Of Heme Oxygenase Gene Expressionmentioning

confidence: 99%

Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

Ryter

Choi

2016

Translational Research

287

214

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The heme oxygenase-1 (HO-1) enzyme system remains an attractive therapeutic target for the treatment of inflammatory conditions. HO-1, a cellular stress protein, serves a vital metabolic function as the rate-limiting step in the degradation of heme to generate carbon monoxide (CO), iron, and biliverdin-IXα (BV) which is converted to bilirubin-IXα (BR). HO-1 may function as a pleiotropic regulator of inflammatory signaling programs, through the generation of its biologically active end-products, namely CO and BV/BR. CO, when applied exogenously, can affect apoptotic, proliferative, and inflammatory cellular programs. Specifically, CO can modulate the production of pro- or anti-inflammatory cytokines and mediators. HO-1/CO may also have immunomodulatory effects with respect to regulating the functions of antigen-presenting cells, dendritic cells, and regulatory T-cells. Therapeutic strategies to modulate HO-1 in disease include the application of natural inducing compounds, as well as gene therapy approaches for the targeted genetic overexpression or knockdown of HO-1. Several compounds have been used therapeutically to inhibit HO activity, including competitive inhibitors of the metalloporphyrin series, or non-competitive isoform-selective derivatives of imidazole-dioxolanes. The end-products of HO activity, BV/BR and CO may be used therapeutically as pharmacological treatments. CO may be applied by inhalation, or through the use of CO releasing molecules (CORMs). This review will discuss HO-1 as a therapeutic target in diseases involving inflammation, including lung and vascular injury, sepsis, ischemia/reperfusion injury and transplant rejection.

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Section: Regulation Of Heme Oxygenase Gene Expressionmentioning

confidence: 99%

Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

Ryter

Choi

2016

Translational Research

287

214

View full text Add to dashboard Cite

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“…To date, there have been a few studies reporting that PRRSV infection could modulate the expression profile of host miRNA (18)(19)(20) and that some miRNAs could influence the replication of PRRSV (18,(21)(22)(23), but there was no report about how PRRSV regulated the expression of miRNA.…”

mentioning

confidence: 99%

MicroRNA 373 Facilitates the Replication of Porcine Reproductive and Respiratory Syndrome Virus by Its Negative Regulation of Type I Interferon Induction

Chen

Shi

Zhang

et al. 2017

J Virol

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MicroRNAs (miRNAs) play an important role in the regulation of immune responses. Previous studies have indicated that dysregulating the miRNAs leads to the immunosuppression of porcine reproductive and respiratory syndrome virus (PRRSV). However, it is not clear how PRRSV regulates the expression of host miRNA, which may lead to immune escape or promote the replication of the virus. The present work suggests that PRRSV upregulated the expression of miR-373 through elevating the expression of specificity protein 1 (Sp1) in MARC-145 cells. Furthermore, this work demonstrated that miR-373 promoted the replication of PRRSV, since miR-373 was a novel negative miRNA for the production of beta interferon (IFN-␤) by targeting nuclear factor IA (NFIA), NFIB, interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, and interferon regulatory factor 1 (IRF1). We also found that both NFIA and NFIB were novel proteins for inducing the production of IFN-␤, and both of them could inhibit the replication of PRRSV. In conclusion, PRRSV upregulated the expression of miR-373 by elevating the expression of Sp1 and hijacked the host miR-373 to promote the replication of PRRSV by negatively regulating the production of IFN-␤.IMPORTANCE PRRSV causes one of the most economically devastating diseases of swine, and there is no effective method for controlling PRRSV. It is not clear how PRRSV inhibits the host's immune response and induces persistent infection. Previous studies have shown that PRRSV inhibited the production of type I IFN, and the treatment of type I IFN could efficiently inhibit the replication of PRRSV, so it will be helpful to design new methods of controlling PRRSV by understanding the molecular mechanism by which PRRSV modulated the production of IFN. The current work shows that miR-373, upregulated by PRRSV, promotes PRRSV replication, since miR-373 impaired the production of IFN-␤ by targeting NFIA, NFIB, IRAK1, IRAK4, and IRF1, and both NFIA and NFIB were antiviral proteins to PRRSV. In conclusion, this paper revealed a novel mechanism of PRRSV that impaired the production of type I IFN by upregulating miR-373 expression in MARC-145 cells.

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“…Our previous study demonstrated that HO-1 could suppress PRRSV replication (15,17). However, the molecular mechanisms of HO-1 inhibition of PRRSV replication are still unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous work showed that overexpression or induction of HO-1 expression inhibits PRRSV and bovine viral diarrhea virus (BVDV) replication (15,16). Furthermore, microRNA miR-24-3p promotes PRRSV replication through suppression of HO-1 expression (17), indicating that increased expression of HO-1 may provide a potential new antiviral strategy against PRRSV infection. However, the molecular mechanism of HO-1 inhibition of PRRSV replication remains unknown.…”

mentioning

confidence: 99%

Carbon Monoxide Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication by the Cyclic GMP/Protein Kinase G and NF-κB Signaling Pathway

Zhang

Zhao

et al. 2017

J Virol

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Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses to the pork industry worldwide each year. Our previous research demonstrated that heme oxygenase-1 (HO-1) can suppress PRRSV replication via an unknown molecular mechanism. In this study, inhibition of PRRSV replication was demonstrated to be mediated by carbon monoxide (CO), a downstream metabolite of HO-1. Using several approaches, we demonstrate that CO significantly inhibited PRRSV replication in both a PRRSV permissive cell line, MARC-145, and the predominant cell type targeted during in vivo PRRSV infection, porcine alveolar macrophages (PAMs). Our results showed that CO inhibited intercellular spread of PRRSV; however, it did not affect PRRSV entry into host cells. Furthermore, CO was found to suppress PRRSV replication via the activation of the cyclic GMP/protein kinase G (cGMP/PKG) signaling pathway. CO significantly inhibits PRRSV-induced NF-B activation, a required step for PRRSV replication. Moreover, CO significantly reduced PRRSV-induced proinflammatory cytokine mRNA levels. In conclusion, the present study demonstrates that CO exerts its anti-PRRSV effect by activating the cellular cGMP/PKG signaling pathway and by negatively regulating cellular NF-B signaling. These findings not only provide new insights into the molecular mechanism of HO-1 inhibition of PRRSV replication but also suggest potential new control measures for future PRRSV outbreaks.IMPORTANCE PRRSV causes great economic losses each year to the swine industry worldwide. Carbon monoxide (CO), a metabolite of HO-1, has been shown to have antimicrobial and antiviral activities in infected cells. Our previous research demonstrated that HO-1 can suppress PRRSV replication. Here we show that endogenous CO produced through HO-1 catalysis mediates the antiviral effect of HO-1. CO inhibits PRRSV replication by activating the cellular cGMP/PKG signaling pathway and by negatively regulating cellular NF-B signaling. These findings not only provide new insights into the molecular mechanism of HO-1 inhibition of PRRSV replication but also suggest potential new control measures for future PRRSV outbreaks.

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MicroRNA miR-24-3p Promotes Porcine Reproductive and Respiratory Syndrome Virus Replication through Suppression of Heme Oxygenase-1 Expression

Cited by 75 publications

References 52 publications

Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

MicroRNA 373 Facilitates the Replication of Porcine Reproductive and Respiratory Syndrome Virus by Its Negative Regulation of Type I Interferon Induction

Carbon Monoxide Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication by the Cyclic GMP/Protein Kinase G and NF-κB Signaling Pathway

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