Viral and host responses to HSV infection

病毒和宿主对 HSV 感染的反应

• 批准号: 7916871
• 负责人: David J Davido
• 金额: $ 9.16万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916871
• 关键词: Acute Promyelocytic Leukemia; Address; Affect; Afferent Neurons; Antiviral Response; Area; Axotomy; Binding; Biochemical; Blindness; Cell Culture Techniques; Cells; Cellular biology; 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; Recurrence; Research; Research Personnel; Role; Severities; Simplexvirus; Site; Stimulus; Stress; Structure; Techniques; Testing; Therapeutic Intervention; Trans-Activators; Transactivation; Viral; Viral Genes; 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; public health relevance; reactivation from latency; response; transcription factor PML; transmission process; ubiquitin-protein ligase; virus host interaction

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.

描述（由申请人提供）：单纯疱疹病毒（HSV）是一种常见且重要的病原体，可引起人类的各种疾病过程，从冷和生殖器疮到失明。 HSV的生命周期有两个不同的阶段：裂解和潜在感染。确定裂解和潜在感染之间切换的关键HSV蛋白是感染细胞蛋白0（ICP0）。 ICP0是一种110 kDa核磷蛋白，可强烈反式激活病毒基因表达，降解核域（ND）10中的细胞蛋白，并抑制细胞干扰素（IFNS）的抗病毒反应。 IFN被分泌为分泌的细胞免疫调节因子，这些因子上调了ND10相关蛋白的表达以限制病毒的扩散和复制。遗传学研究表明，与ND10相关的蛋白质蛋白质细胞性白血病（PML）在IFN介导的HSV复制抑制中起着重要作用。因此，ICP0，PML和IFN之间的相互作用很可能控制HSV的感染类型。 ICP0和PML在病毒宿主对感染中所需的机制和域在很大程度上尚不确定。我们研究的长期目标是在分子水平上了解病毒 - 细胞相互作用如何影响HSV感染。该建议的目的是确定ICP0和PML上的特定基序如何调节病毒宿主反应。我们的中心假设是ICP0会损害PML的抗病毒活性，而PML的抗病毒活性反过来是有效的病毒复制所必需的。为了检验这一假设，我们将使用各种遗传，生化和细胞生物学技术来识别参与调节HSV复制的ICP0和PML的基序。我们的研究结果预计将导致新型的抗病毒疗法抑制或限制HSV疾病的严重程度。为此，我们的三个具体目的是：1）确定PML基序在IFN对HSV感染反应中的贡献，2）识别ICP0中的域和位点，以抵消宿主防御感染对感染的影响； 3）确定ICP0-PML相互作用在调节细胞抗病毒抗病毒药物中的作用。这项研究的公共卫生相关性是HSV感染是西方工业化国家传染性失明的主要原因。从这些研究中，我们希望确定并表征HSV（ICP0）及其宿主（IFN和PML）之间的关键连接，这些连接确定了HSV类型的HSV将建立。这些结果可用于开发新型的抗HSV处理。