Abstract
Major gaps in our knowledge of pathogen genes and how these gene products interact with host gene products to cause disease represent a major obstacle to progress in vaccine and antiviral drug development for the herpesviruses. To begin to bridge these gaps, we conducted a dual analysis of Murine Cytomegalovirus (MCMV) and host cell transcriptomes during lytic infection. We analyzed the MCMV transcriptome during lytic infection using both classical cDNA cloning and sequencing of viral transcripts and next generation sequencing of transcripts (RNA-Seq). We also investigated the host transcriptome using RNA-Seq combined with differential gene expression analysis, biological pathway analysis, and gene ontology analysis.We identify numerous novel spliced and unspliced transcripts of MCMV. Unexpectedly, the most abundantly transcribed viral genes are of unknown function. We found that the most abundant viral transcript, recently identified as a noncoding RNA regulating cellular microRNAs, also codes for a novel protein. To our knowledge, this is the first viral transcript that functions both as a noncoding RNA and an mRNA. We also report that lytic infection elicits a profound cellular response in fibroblasts. Highly upregulated and induced host genes included those involved in inflammation and immunity, but also many unexpected transcription factors and host genes related to development and differentiation. Many top downregulated and repressed genes are associated with functions whose roles in infection are obscure, including host long intergenic noncoding RNAs, antisense RNAs or small nucleolar RNAs. Correspondingly, many differentially expressed genes cluster in biological pathways that may shed new light on cytomegalovirus pathogenesis. Together, these findings provide new insights into the molecular warfare at the virus-host interface and suggest new areas of research to advance the understanding and treatment of cytomegalovirus-associated diseases.
Highlights
The cytomegaloviruses, classified within the Betherpesvirinae subfamily, are a group of species-specific herpes viruses that establish life-long infection of their hosts
We report a comprehensive analysis of the Murine Cytomegalovirus (MCMV) transcriptome during lytic infection derived from cloning and sequencing of viral transcripts and generation sequencing (RNA-Seq)
The major findings are as follows: 1) The MCMV transcriptome diverges substantially from that predicted by current annotation; 2) the identification of a novel viral protein specified by the most abundant viral transcript (MAT) transcript indicates that this transcript functions as an mRNA and a non-coding RNA; 3) the majority of the most abundantly transcribed viral genes are of unknown function; and 4) the host response to infection includes regulation of many host genes and gene networks of unknown relevance to infection
Summary
The cytomegaloviruses, classified within the Betherpesvirinae subfamily, are a group of species-specific herpes viruses that establish life-long infection of their hosts. Human cytomegalovirus (HCMV) can cause devastating disease and death in congenitallyinfected infants, and long-term neurological complications in survivors. HCMV has been linked to lung injury in trauma patients [3] and is postulated to act as a cofactor in atherosclerosis and some cancers [4,5]. For these reasons, there is an urgent need for an effective vaccine and new antiviral intervention strategies that mitigate the toxicity and drug resistance shortcomings of current antiviral drugs [1,6]. Despite the publication of the first sequence of the HCMV genome in 1990 [7,8], and the first sequence of the murine cytomegalovirus (MCMV) genome in 1996 [9], there are still important questions regarding the nature and number of genes for these viruses
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