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Two microRNAs encoded within the bovine herpesvirus 1 latency-related gene promote cell survival by interacting with RIG-I and stimulating NF-?B-dependent transcription and beta interferon signaling pathways.

ABSTRACT: Sensory neurons latently infected with bovine herpesvirus 1 (BHV-1) abundantly express latency-related (LR) RNA (LR-RNA). Genetic evidence indicates that LR protein expression plays a role in the latency-reactivation cycle, because an LR mutant virus that contains three stop codons downstream of the first open reading frame (ORF2) does not reactivate from latency. The LR mutant virus induces higher levels of apoptotic neurons in trigeminal ganglia, and ORF2 interferes with apoptosis. Although ORF2 is important for the latency-reactivation cycle, other factors encoded by the LR gene are believed to play a supportive role. For example, two microRNAs (miRNAs) encoded within the LR gene are expressed in trigeminal ganglia of latently infected calves. These miRNAs interfere with bICP0 protein expression and productive infection in transient-transfection assays. In this report, we provide evidence that the two LR miRNAs cooperate with poly(I·C), interferon (IFN) regulatory factor 3 (IRF3), or IRF7 to stimulate beta interferon (IFN-?) promoter activity. Both miRNAs also stimulated IFN-? promoter activity and nuclear factor-kappa B (NF-?B)-dependent transcription when cotransfected with a plasmid expressing retinoic acid-inducible gene I (RIG-I). In the presence of RIG-I, the LR miRNAs enhanced survival of mouse neuroblastoma cells, which correlated with activation of the antiapoptosis cellular transcription factor, NF-?B. Immunoprecipitation assays demonstrated that both miRNAs stably interact with RIG-I, suggesting that this interaction directly stimulates the RIG-I signaling pathway. In summary, the results of these studies suggest that interactions between LR miRNAs and RIG-I promote the establishment and maintenance of latency by enhancing survival of infected neurons.

SUBMITTER: Silva LF

PROVIDER: S-EPMC3264334 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Two microRNAs encoded within the bovine herpesvirus 1 latency-related gene promote cell survival by interacting with RIG-I and stimulating NF-κB-dependent transcription and beta interferon signaling pathways.

Silva Leticia Frizzo da LF Jones Clinton C

Journal of virology 20111130 3

Sensory neurons latently infected with bovine herpesvirus 1 (BHV-1) abundantly express latency-related (LR) RNA (LR-RNA). Genetic evidence indicates that LR protein expression plays a role in the latency-reactivation cycle, because an LR mutant virus that contains three stop codons downstream of the first open reading frame (ORF2) does not reactivate from latency. The LR mutant virus induces higher levels of apoptotic neurons in trigeminal ganglia, and ORF2 interferes with apoptosis. Although OR ...[more]

PMID: 22130548

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Project description:UnlabelledGammaherpesviruses, including Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV, or HHV-8), and murine gammaherpesvirus 68 (MHV68, γHV68, or MuHV-4), are B cell-tropic pathogens that each encode at least 12 microRNAs (miRNAs). It is predicted that these regulatory RNAs facilitate infection by suppressing host target genes involved in a wide range of key cellular pathways. However, the precise contribution that gammaherpesvirus miRNAs make to viral life cycle and pathogenesis in vivo is unknown. MHV68 infection of mice provides a highly useful system to dissect the function of specific viral elements in the context of both asymptomatic infection and disease. Here, we report (i) analysis of in vitro and in vivo MHV68 miRNA expression, (ii) generation of an MHV68 miRNA mutant with reduced expression of all 14 pre-miRNA stem-loops, and (iii) comprehensive phenotypic characterization of the miRNA mutant virus in vivo. The profile of MHV68 miRNAs detected in infected cell lines varied with cell type and did not fully recapitulate the profile from cells latently infected in vivo. The miRNA mutant virus, MHV68.Zt6, underwent normal lytic replication in vitro and in vivo, demonstrating that the MHV68 miRNAs are dispensable for acute replication. During chronic infection, MHV68.Zt6 was attenuated for latency establishment, including a specific defect in memory B cells. Finally, MHV68.Zt6 displayed a striking attenuation in the development of lethal pneumonia in mice deficient in IFN-γ. These data indicate that the MHV68 miRNAs may facilitate virus-driven maturation of infected B cells and implicate the miRNAs as a critical determinant of gammaherpesvirus-associated disease.ImportanceGammaherpesviruses such as EBV and KSHV are widespread pathogens that establish lifelong infections and are associated with the development of numerous types of diseases, including cancer. Gammaherpesviruses encode many small noncoding RNAs called microRNAs (miRNAs). It is predicted that gammaherpesvirus miRNAs facilitate infection and disease by suppressing host target transcripts involved in a wide range of key cellular pathways; however, the precise contribution that these regulatory RNAs make to in vivo virus infection and pathogenesis is unknown. Here, we generated a mutated form of murine gammaherpesvirus (MHV68) to dissect the function of gammaherpesvirus miRNAs in vivo. We demonstrate that the MHV68 miRNAs were dispensable for short-term virus replication but were important for establishment of lifelong infection in the key virus reservoir of memory B cells. Moreover, the MHV68 miRNAs were essential for the development of virus-associated pneumonia, implicating them as a critical component of gammaherpesvirus-associated disease.

Dataset Information

Two microRNAs encoded within the bovine herpesvirus 1 latency-related gene promote cell survival by interacting with RIG-I and stimulating NF-?B-dependent transcription and beta interferon signaling pathways.

Publications

Two microRNAs encoded within the bovine herpesvirus 1 latency-related gene promote cell survival by interacting with RIG-I and stimulating NF-κB-dependent transcription and beta interferon signaling pathways.

Similar Datasets

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