The long-term goal of my laboratory is to identify new targets for control of cytomegalovirus (CMV) infection. Although infection is usually asymptomatic, CMV can cross the placenta and is the most common viral cause of birth defects in humans. Immunocompromised individuals, such as transplant recipients and AIDS patients are also at high risk for disease and death due to CMV. Because human CMV only infects humans, animal models such as murine cytomegalovirus (MCMV) are important tools to study viral gene function. Despite the extensive use of MCMV as a model system for HCMV, certain areas of research have received little attention in MCMV compared to HCMV. One of these areas is gene regulation. We have identified two genes, m142 and m143, which are essential for MCMV and have homologues in HCMV. The proteins inhibit a specific host defense mechanism. Expression of these essential viral proteins is controlled at both the transcriptional and post-transcriptional level. Regulation of transcription is mediated by both cellular and viral factors which have not been identified. The processes involved in the post-transcriptional regulation are also currently unknown.
The specific aim of this project is to identify the specific cellular and viral factors involved in this regulation. This will be done by deletional and mutational analysis of the promoters in a luciferase reporter system followed by electromobility gel shift analysis and chromatin immunoprecipitation assays. For analysis of post-transcriptional regulator mechanisms mRNA localization and stability analyses will be performed. Understanding of both the cellular and viral regulators of these genes which are essential for the virus will not only expand our understanding of MCMV gene regulation in general, but also may provide the basis for rational design of novel therapies to treat or prevent CMV infections.
Studies of essential CMV genes provide the basis for rational design of novel therapies to treat or prevent CMV infections. Knowledge of how essential genes are regulated will also enhance our understanding of CMV reactivation from latency, a molecular event with significant clinical impact.