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A leaderless genome identified during persistent bovine coronavirus infection is associated with attenuation of gene expression.

ABSTRACT: The establishment of persistent viral infection is often associated with the selection of one or more mutant viruses. For example, it has been found that an intraleader open reading frame (ORF) in genomic and subgenomic mRNA (sgmRNA) molecules is selected during bovine coronavirus (BCoV) persistence which leads to translation attenuation of the downstream ORF. Here, we report the unexpected identification of leaderless genomes, in addition to leader-containing genomes, in a cell culture persistently infected with BCoV. The discovery was made by using a head-to-tail ligation method that examines genomic 5'-terminal sequences at different times postinfection. Functional analyses of the leaderless genomic RNA in a BCoV defective interfering (DI) RNA revealed that (1) the leaderless genome was able to serve as a template for the synthesis of negative-strand genome, although it cannot perform replicative positive-strand genomic RNA synthesis, and (2) the leaderless genome retained its function in translation and transcription, although the efficiency of these processes was impaired. Therefore, this previously unidentified leaderless genome is associated with the attenuation of genome expression. Whether the leaderless genome contributes to the establishment of persistent infection remains to be determined.

SUBMITTER: Ke TY

PROVIDER: S-EPMC3861326 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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A leaderless genome identified during persistent bovine coronavirus infection is associated with attenuation of gene expression.

Ke Ting-Yung TY Liao Wei-Yu WY Wu Hung-Yi HY

PloS one 20131212 12

The establishment of persistent viral infection is often associated with the selection of one or more mutant viruses. For example, it has been found that an intraleader open reading frame (ORF) in genomic and subgenomic mRNA (sgmRNA) molecules is selected during bovine coronavirus (BCoV) persistence which leads to translation attenuation of the downstream ORF. Here, we report the unexpected identification of leaderless genomes, in addition to leader-containing genomes, in a cell culture persiste ...[more]

PMID: 24349214

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Project description:BackgroundIntestinal fibrosis is a common and serious complication of Crohn's disease characterized by the accumulation of fibroblasts, deposition of extracellular matrix, and formation of scar tissue. Although many factors including cytokines and proteases contribute to the development of intestinal fibrosis, the initiating mechanisms and the complex interplay between these factors remain unclear.MethodsChronic infection of mice with Salmonella enterica serovar Typhimurium was used to induce intestinal fibrosis. A murine protease-specific CLIP-CHIP microarray analysis was employed to assess regulation of proteases and protease inhibitors. To confirm up- or downregulation during fibrosis, we performed quantitative real-time polymerase chain reaction (PCR) and immunohistochemical stainings in mouse tissue and tissue from patients with inflammatory bowel disease. In vitro infections were used to demonstrate a direct effect of bacterial infection in the regulation of proteases.ResultsMice develop severe and persistent intestinal fibrosis upon chronic infection with Salmonella enterica serovar Typhimurium, mimicking the pathology of human disease. Microarray analyses revealed 56 up- and 40 downregulated proteases and protease inhibitors in fibrotic cecal tissue. Various matrix metalloproteases, serine proteases, cysteine proteases, and protease inhibitors were regulated in the fibrotic tissue, 22 of which were confirmed by quantitative real-time PCR. Proteases demonstrated site-specific staining patterns in intestinal fibrotic tissue from mice and in tissue from human inflammatory bowel disease patients. Finally, we show in vitro that Salmonella infection directly induces protease expression in macrophages and epithelial cells but not in fibroblasts.ConclusionsIn summary, we show that chronic Salmonella infection regulates proteases and protease inhibitors during tissue fibrosis in vivo and in vitro, and therefore this model is well suited to investigating the role of proteases in intestinal fibrosis.

Project description:Bovine coronavirus (BCoV) infection that causes disease outbreaks among farm animals, resulting in significant economic losses particularly in the cattle industry, has the potential to become zoonotic. miRNAs, which are short non-coding segments of RNA that inhibits the expression of their target genes, have been identified as potential biomarkers and drug targets, though this potential in BCoV remains largely unknown. We hypothesize that certain miRNAs could simultaneously target multiple genes, are significantly conserved across many species, thereby demonstrating the potential to serve as diagnostic or therapeutic tools for bovine coronavirus infection. To this end, we utilized different existing and publicly available computational tools to conduct system analysis predicting important miRNAs that could affect BCoV pathogenesis. Eleven genes including CEBPD, IRF1, TLR9, SRC, and RHOA, significantly indicated in immune-related pathways, were identified to be associated with BCoV, and implicated in other coronaviruses. Of the 70 miRNAs predicted to target the identified genes, four concomitant miRNAs (bta-miR-11975, bta-miR-11976, bta-miR-22-3p, and bta-miR-2325c) were found. Examining the gene interaction network suggests IL-6, IRF1, and TP53 as key drivers. Phylogenetic analysis revealed that miR-22 was completely conserved across all 14 species it was searched against, suggesting a shared and important functional role. Functional annotation and associated pathways of target genes, such as positive regulation of cytokine production, IL-6 signaling pathway, and regulation of leukocyte differentiation, indicate the miRNAs are major participants in multiple aspects of both innate and adaptive immune response. Examination of variants evinced a potentially deleterious SNP in bta-miR-22-3p and an advantageous SNP in bta-miR-2325c. Conclusively, this study provides new insight into miRNAs regulating genes responding to BCoV infection, with bta-miR-22-3p particularly indicated as a potential drug target or diagnostic marker for bovine coronavirus.

Dataset Information

A leaderless genome identified during persistent bovine coronavirus infection is associated with attenuation of gene expression.

Publications

A leaderless genome identified during persistent bovine coronavirus infection is associated with attenuation of gene expression.

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