Alterations of Cellular Gene Expression in Marek's Disease Virus Latently Infected Cells

After an initial phase of active replication herpesviruses enter a latent state of infection characterized by little to no nascent virus production.  Active virus production can be reactivated by environmental stressors.  In addition latent herpesvirus infections can lead to cellular transformation.  Marek's Disease Virus (MDV), an alphaherpesvirus, is the causative agent of Marek's Disease (MD), a lymphoproliferative disorder of chickens.  To better understand the cellular genes involved in MDV latency and transformation small RNA deep sequencing and microarray analysis were utilized to identify changes in microRNA (miRNA) and mRNA expression, respectively, in MDV latently infected cells.  Several cellular miRNAs, including miR-92, miR-125b, miR-147, and miR-146b, were found differentially expressed in MDV lymphblastoid cell lines (MSB1, RP2, and CU115) upon viral reactivation as well as in MDV-induced tumorgenic spleens, indicating that these miRNAs are likely involved in MDV latency.  In silico target analysis suggests that these miRNAs have the potential to regulate multiple cellular pathways, including the cell cycle, apoptosis, MAPK signaling, and ubiquitin mediated proteolysis.  Microarray analysis of changes in cellular mRNA expression levels upon chemically-induced MDV reactivation from latency in MDV lymphblastoid cell lines identified over  hundred genes are differentially expressed within the first 24 hours of viral reactivation.  Many of these differentially expressed genes are involved in cell cycle and apoptotic pathways, as well as in DNA metabolism, and lymphocyte differentiation.  Taken together we have shown that numerous cellular miRNAs and genes are involved in the maintenance of MDV latency and transformation.