Modulation of Interferon Signaling Pathways by the Human Cytomegalovirus Immediate-Early 1 Protein

• Applicant: Dr. Christina Paulus
• Subject Area: Virology
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 216996086

Human cytomegalovirus (hCMV) is a leading cause of birth defects and of severe disease in immunocompromised patients. The pathogenesis of hCMV disease is commonly linked to adverse (innate) immune responses. At the molecular level, this is reflected by the fact that the virus alters expression of numerous immune regulatory host genes. Many of these genes are responsive to type I and/or type II interferons (IFNs) and subject to regulation by cellular signal transducer and activator of transcription (STAT) proteins. Our work has shown that the 72-kDa immediate-early 1 protein (IE1) of hCMV targets human STAT2 to block type I IFN-regulated anti-viral signaling and gene expression. At the same time, IE1 activates pro-inflammatory and immune stimulatory host genes normally controlled by type II IFN through a STAT1-dependent mechanism. The proposed project will specify the molecular requirements underlying the differential effects of IE1 on STAT-dependent IFN pathways. In addition, we will elucidate the impact of the type II IFN-like response to IE1 on the course and outcome of productive and latent hCMV infection. Importantly, we will not only consider the established anti-viral role of IFN responses, but also the emerging concept that the virus may divert components of these pathways to its own benefit. Our results will provide important insights into the function of a viral key regulator and into the molecular events of hCMV pathogenesis thereby facilitating new anti-viral strategies destined to reduce the huge health-related and economic burden associated with this virus.

• DFG Programme: Research Grants