Viral and host responses to HSV infection

病毒和宿主对 HSV 感染的反应

基本信息

批准号：
7318513
负责人：
David J Davido
金额：
$ 33.32万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7318513
关键词：
Acute Promyelocytic Leukemia Address Affect Afferent Neurons Antiviral Response Area Axotomy Binding Biochemical Genetics Blindness Cells Cellular biology Cultured Cells Data Developed Countries Development Disease Epithelial Cells Event Fibroblasts Gene Expression Genetic Genetic Screening Genital system Goals Health Heat-Shock Response Host Defense Human Immediate-Early Proteins Immune response Infection Infectious Disease Immunology Integration Host Factors Interferon Receptor Interferons Intervention Lead Link Lytic Lytic Phase Maps Mediating Molecular Mus Nuclear Oral cavity Pathology Penetration Phase Phosphoproteins Phosphorylation Phosphorylation Site Play Post-Translational Protein Processing Process Proteins Public Health Purpose Range Recurrence Research Research Personnel Role Severities Simplexvirus Site Stimulus Stress Structure Techniques Testing Therapeutic Intervention Trans-Activators Transactivation Viral Viral Physiology Viral Proteins Virus Virus Diseases Virus Replication Virus-Cell Membrane Interaction Work experience improved in vivo innovation latent infection mouse model multidisciplinary mutant novel pathogen prevent programs protein expression reactivation from latency response transcription factor PML transmission process ubiquitin-protein ligase virus host interaction

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) is a common and significant pathogen which causes a variety of disease processes in humans, ranging from cold and genital sores to blindness. The lifecycle of HSV has two distinct phases: lytic and latent infections. A pivotal HSV protein in determining the switch between lytic and latent infections is infected cell protein 0 (ICP0). ICP0 is a 110-KDa nuclear phosphoprotein that strongly transactivates viral gene expression, degrades cellular proteins in nuclear domain (ND) 10, and inhibits the anti-viral response of cellular interferons (IFNs). IFNs are secreted cellular immunomodulatory factors that upregulate the expression of ND10-associated proteins to limit the spread and replication of viruses. Genetics studies have indicated that the ND10-associated protein, promyelocytic leukemia (PML), plays an important role in IFN-mediated inhibition of HSV replication. Thus, it is likely that the interactions between ICP0, PML, and IFNs govern the type of infection HSV will establish. The mechanisms and domains on ICP0 and PML required in virus-host responses to infection through IFNs have been largely undetermined. The long-term objective of our studies is to understand at the molecular level how virus-cell interactions affect HSV infection. The objective of this proposal is to determine how specific motifs on ICP0 and PML modulate the virus-host response. Our central hypothesis is that ICP0 impairs the anti-viral activity of PML, which, in turn, is required for efficient viral replication. To test this hypothesis, we will use a variety of genetic, biochemical, and cell biology techniques to identify motifs on ICP0 and PML that participate in regulating HSV replication. Results from our studies are expected to lead to novel anti-viral therapies that inhibit or limit the severity of HSV diseases. For this purpose, our three Specific Aims are to: 1) Determine the contribution of PML motifs in the IFN response to HSV infection, 2) Identify domains in and sites on ICP0 that serve to counteract host defenses to infection, and 3) Determine the role of ICP0-PML interactions in modulating the cellular anti-viral response. The public health relevance of this research is that HSV infections are the primary cause of infectious blindness in western industrialized countries. From these studies, we expect to identify and characterize crucial connections between HSV (ICP0) and its host (IFN and PML) that determine the type infection HSV will establish. These results may be used to develop novel anti-HSV treatments.