Abstract
Herpesvirus-encoded microRNAs (miRNAs) have been discovered in infected cells; however, lack of a suitable animal model has hampered functional analyses of viral miRNAs in vivo. Marek’s disease virus (MDV) (Gallid alphaherpesvirus 2, GaHV-2) genome contains 14 miRNA precursors, which encode 26 mature miRNAs, grouped into three clusters. In this study, the role of MDV-encoded cluster 3 miRNAs, also known as mdv1-miR-M8-M10, in pathogenesis was evaluated in chickens, the natural host of MDV. Our results show that deletion of cluster 3 miRNAs did not affect virus replication and plaque size in cell culture, but increased early cytolytic replication of MDV in chickens. We also observed that deletion of cluster 3 miRNAs resulted in significantly higher virus reactivation from peripheral blood lymphocytes. In addition, pathogenesis studies showed that deletion of cluster 3 miRNAs resulted in more severe atrophy of lymphoid organs and reduced mean death time, but did not affect the incidence of MDV-associated visceral tumors. We confirmed these results by generating a cluster 3 miRNA revertant virus in which the parental MDV phenotype was restored. To the best of our knowledge, our study provides the first evidence that MDV cluster 3 miRNAs play an important role in modulating MDV pathogenesis.
Highlights
MicroRNAs are approximately 22 nucleotide-long, non-coding RNAs that have been identified in animals, plants, and viruses. miRNAs associate with complementary sites in target mRNAs to regulate their post-transcriptional processes by inducing mRNA degradation and translation inhibition [1]
Using chickens as the viral host model, we demonstrate that cluster 3 miRNAs are actively involved in Marek’s disease virus (MDV) early cytolytic infection and may contribute to reactivation, and play a role in limiting MDV pathogenesis
As cluster 3 miRNAs fall within the 16 kb-long fragments of SalI digestion products, which cannot be resolved in 1% agarose gel, no differences in SalI digestion fragments were observed among parental, deletion, and revertant bacterial artificial chromosome (BAC) DNA (Figure 1B, lanes 4–6)
Summary
MicroRNAs (miRNAs) are approximately 22 nucleotide-long, non-coding RNAs that have been identified in animals, plants, and viruses. miRNAs associate with complementary sites in target mRNAs to regulate their post-transcriptional processes by inducing mRNA degradation and translation inhibition [1]. Numerous studies have revealed the importance of miRNAs in virus infection [2,3,4]. Most herpesviruses, including herpes simplex virus (HSV), Epstein–Barr virus (EBV), Kaposi’s sarcoma-associated virus (KSHV), and Marek’s disease virus (MDV), encode miRNAs, indicating the important role of miRNAs in diverse hosts [5,6,7,8]. EBV- and KSHV-encoded miRNAs have been shown to be important for viral transformation and oncogenesis [9,10,11]. The lack of suitable natural infectious animal models has limited the direct functional analyses of viral miRNAs in vivo. MDV, an avian oncogenic alphaherpesvirus that causes a highly contagious neoplastic disease in chickens, is an ideal infectious model for herpesvirus related cancer research. Marek’s disease (MD) is Viruses 2020, 12, 1317; doi:10.3390/v12111317 www.mdpi.com/journal/viruses
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