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Host miR-26a suppresses replication of porcine reproductive and respiratory syndrome virus by upregulating type I interferons.

ABSTRACT: MicroRNAs (miRNAs) play important roles in viral infections, especially by modulating the expression of cellular factors essential to viral replication or the host innate immune response to infection. To identify host miRNAs important to controlling porcine reproductive and respiratory syndrome virus (PRRSV) infection, we screened 15 miRNAs that were previously implicated in innate immunity or antiviral functions. Over-expression of the miR-26 family strongly inhibited PRRSV replication in vitro, as shown by virus titer assays, Western blotting, and qRT-PCR assays. MiR-26a inhibited the replication of both type 1 and type 2 PRRSV strains. Mutating the seed region of miR-26 restored viral titers. Luciferase reporters showed that miR-26a does not target the PRRSV genome directly but instead affects the expression of type I interferon and the IFN-stimulated genes MX1 and ISG15 during PRRSV infection. These results demonstrate the important role of miR-26a in modulating PRRSV infection and also support the possibility of using host miR-26a to achieve RNAi-mediated antiviral therapeutic strategies.

SUBMITTER: Li L

PROVIDER: S-EPMC7114497 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Host miR-26a suppresses replication of porcine reproductive and respiratory syndrome virus by upregulating type I interferons.

Li Liwei L Wei Zuzhang Z Zhou Yanjun Y Gao Fei F Jiang Yifeng Y Yu Lingxue L Zheng Hao H Tong Wu W Yang Shen S Zheng Haihong H Shan Tongling T Liu Fei F Xia Tianqi T Tong Guangzhi G

Virus research 20140916

MicroRNAs (miRNAs) play important roles in viral infections, especially by modulating the expression of cellular factors essential to viral replication or the host innate immune response to infection. To identify host miRNAs important to controlling porcine reproductive and respiratory syndrome virus (PRRSV) infection, we screened 15 miRNAs that were previously implicated in innate immunity or antiviral functions. Over-expression of the miR-26 family strongly inhibited PRRSV replication in vitro ...[more]

PMID: 25218480

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Project description:UnlabelledPorcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important viruses affecting the swine industry worldwide. Our previous research showed that PRRSV downregulates the expression of heme oxygenase-1 (HO-1), a pivotal cytoprotective enzyme, postinfection and that overexpression of HO-1 inhibits PRRSV replication. MicroRNAs regulate gene expression at the posttranscriptional level and have recently been demonstrated to play vital roles in pathogen-host interactions. The present study sought to determine whether microRNAs modulate HO-1 expression and, by doing so, regulate PRRSV replication. Using bioinformatic prediction and experimental verification, we demonstrate that HO-1 expression is regulated by miR-24-3p. A direct interaction between miR-24-3p and HO-1 mRNA was confirmed using a number of approaches. Overexpression of miR-24-3p significantly decreased HO-1 mRNA and protein levels. PRRSV infection induced miR-24-3p expression to facilitate viral replication. The suppressive effect of HO-1 induction by protoporphyrin IX cobalt chloride (CoPP; a classical inducer of HO-1 expression) on PRRSV replication in MARC-145 cells and primary porcine alveolar macrophages could also be reversed by overexpression of miR-24-3p. Collectively, these results suggested that miR-24-3p promotes PRRSV replication through suppression of HO-1 expression, which not only provides new insights into virus-host interactions during PRRSV infection but also suggests potential new antiviral strategies against PRRSV infection.ImportanceMicroRNAs (miRNAs) play vital roles in viral infections by regulating the expression of viral or host genes at the posttranscriptional level. Heme oxygenase-1 (HO-1), a pivotal cytoprotective enzyme, has antiviral activity for a number of viruses, such as Ebola virus, hepatitis C virus, human immunodeficiency virus, and our focus, PRRSV, which causes great economic losses each year in the swine industry worldwide. Here, we show that PRRSV infection induces host miRNA miR-24-3p expression and that miR-24-3p regulates HO-1 expression through both mRNA degradation and translation repression. Suppression of HO-1 expression by miR-24-3p facilitates PRRSV replication. This work lends credibility to the hypothesis that an arterivirus can manipulate cellular miRNAs to enhance virus replication by regulating antiviral responses following viral infection. Therefore, our findings provide new insights into the pathogenesis of PRRSV.

Project description:Porcine Reproductive and Respiratory Syndrome (PRRS) is historically the most economically important swine disease worldwide that severely affects the reproductive performance of sows. However, little is still known about the genetic basis of reproductive performance in purebred herds during a PRRS outbreak through the comparison of maternal and terminal breeds. Thus, the objective of this work was to explore the host genetics of response to PRRS in purebred sows from two breeds. Reproductive data included 2546 Duroc and 2522 Landrace litters from 894 and 813 purebred sows, respectively, which had high-density genotype data available (29,799 single nucleotide polymorphisms; SNPs). The data were split into pre-PRRS, PRRS, and post-PRRS phases based on standardized farrow-year-week estimates. Heritability estimates for reproductive traits were low to moderate (≤0.20) for Duroc and Landrace across PRRS phases. On the other hand, genetic correlations of reproductive traits between PRRS phases were overall moderate to high for both breeds. Several associations between MARC0034894, a candidate SNP for response to PRRS, with reproductive performance were identified (P-value < 0.05). Genomic analyses detected few QTL for reproductive performance across all phases, most explaining a small percentage of the additive genetic variance (≤8.2%, averaging 2.1%), indicating that these traits are highly polygenic. None of the identified QTL within a breed and trait overlapped between PRRS phases. Overall, our results indicate that Duroc sows are phenotypically more resilient to PRRS than Landrace sows, with a similar return to PRRS-free performance between breeds for most reproductive traits. Genomic prediction results indicate that genomic selection for improved reproductive performance under a PRRS outbreak is possible, especially in Landrace sows, by training markers using data from PRRS-challenged sows. On the other hand, the high genetic correlations with reproductive traits between PRRS phases suggest that selection for improved reproductive performance in a clean environment could improve performance during PRRS, but with limited efficiency due to their low heritability estimates. Thus, we hypothesize that an indicator trait that could be indirectly selected to increase the response to selection for these traits would be desirable and would also improve the reproductive performance of sows during a PRRS outbreak.

Dataset Information

Host miR-26a suppresses replication of porcine reproductive and respiratory syndrome virus by upregulating type I interferons.

Publications

Host miR-26a suppresses replication of porcine reproductive and respiratory syndrome virus by upregulating type I interferons.

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