Abstract

Human cytomegalovirus (HCMV) can cause considerable disease and even death in infected infants and in persons with impaired immunity.  HCMV infections are especially important in transplant patients, who may suffer graft loss, vascular disease, hepatitis, and pneumonitis. Due to the species specificity of CMVs, infection of mice with murine cytomegalovirus (MCMV) is the best model system to study these diseases and to test new strategies to control CMV infections.  Currently, there is no effective vaccine available to prevent infections.  Also, very little is known about the specific mechanisms by which these viruses cause disease.  We propose to use the mouse model to address these problems by characterizing the entire MCMV transcriptome. Specifically, we will directly analyze all of the viral transcription products that accumulate in infected cells. Preliminary studies indicate that we will discover many novel and complex genes that could herald a paradigm shift in our understanding of herpesvirus biology.

In the next phase, we will use this information to investigate how expression of viral genes relates to diseases caused by CMV. Specifically, we will test whether different diseases caused by this virus are associated with specific gene expression programs.  To accomplish this, we will generate viral gene arrays on glass chips (microarrays) that represent all of the transcripts discovered in the first study. These arrays will enable us to perform high-throughput experiments required to simultaneously study all the virus genes expressed in tissues and organs of infected mice.  We will also determine whether and how viral gene programs are altered under conditions where mice are experimentally immunosuppressed.  Generating detailed viral gene expression maps may yield important breakthroughs in understanding how these viruses cause disease. These studies may also provide critical information we could use to test new treatments and vaccines strategies to control CMV infections.

Transcriptomics is an emerging field of research that focuses on defining genes and understanding how genes are expressed and regulated. Technologies available for transcriptome research are rapidly evolving as are integrated information technology solutions for data storage and analysis. In the final phase we will integrate our transcriptome data with available bioinformatics software and we will collaborate with IT researchers to develop novel bioinformatics platforms for this project. The goal of these efforts will be to develop a publicly accessible database of the cytomegalovirus transcriptome.  We envision this database to serve as the definitive resource for the worldwide research community working to understand the evolution and pathogenesis of herpes viruses.