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The role of repressive nuclear bodies in latent herpes simplex virus infection

抑制核体在潜伏单纯疱疹病毒感染中的作用

基本信息

批准号：
9758467
负责人：
JON Blackburn SUZICH
金额：
$ 3.37万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9758467
关键词：
ATRX gene Acute Promyelocytic Leukemia Afferent Neurons Antiviral Agents Axon Blepharitis Blindness Cells Cellular Structures Chemistry Chromatin Structure Conjunctivitis Cornea Data Development Disease Environment Epithelial Cells Equilibrium Experimental Models Exposure to Eye Infections Eye diseases Foundations Future Ganglia Gene Silencing Genetic Transcription Genome Goals Head and neck structure Herpesviridae Herpesvirus 1 Herpetic Keratitis Heterochromatin Heterogeneity Human Image Immune response In Vitro Infection Inflammatory Response Interferon Type I Interferons Keratitis Knock-out Lead Life Long-Term Effects LoxP-flanked allele Lytic Phase Maintenance Microfluidics Modeling Morbidity - disease rate Mus Neuroglia Neurons Nuclear Nuclear Structure Peripheral Phase Physicians Play Population Proteins Recurrence Recurrent disease Refractory Resolution Role Scientist Simplexvirus Stimulus Testing Viral Genes Viral Genome Virus Virus Diseases Virus Shedding Western World base career clinically relevant corneal epithelium corneal scar experience histone modification human pathogen in vivo in vivo Model insight knock-down latent infection lytic replication neuronal cell body novel pathogen preservation prevent response therapeutic target transmission process virology

项目摘要

PROJECT SUMMARY/ABSTRACT Herpes simplex virus type 1 (HSV-1) is a ubiquitous human pathogen that is present in up to 90% of the world’s population. HSV-1 persists for life in the form of a latent infection in the peripheral ganglia that innervate the head and neck. Reactivation of HSV-1 from latent infection is associated with significant morbidity, including herpetic eye disease which can manifest as conjunctivitis, blepharitis or corneal epithelial and stromal keratitis. Recurrent ocular reactivation of the virus can result in recurrent herpetic keratitis, which remains the leading cause of infectious blindness in the developed world. Therefore, there is a need to understand how the virus remains latent in neurons to ultimately prevent reactivation and recurrent infection. During latency, the viral genome is associated with repressive nuclear structures and is assembled into heterochromatin. The role of cellular heterochromatin-associated proteins in maintaining HSV-1 latency is not known. I have identified one cellular protein, ATRX, that is essential for maintaining HSV-1 latency. In Aim 1 of this proposal, I will utilize a novel primary neuronal model of HSV-1 latency that permits the establishment of a latent infection in peripheral neurons cultured in microfluidic chambers. I will test the hypothesis that ATRX is the key cellular protein involved in preserving HSV-1 latency and examine how ATRX maintains heterochromatin-based gene silencing. In addition, I will utilize an ocular model of infection to understand the effects of ATRX depletion in vivo. These studies will provide mechanistic insights into the contribution of heterochromatin-based silencing in maintaining HSV-1 latency and preventing recurrent reactivation. There is considerable heterogeneity at the neuronal level in the co-localization of viral genomes with different nuclear domains, likely resulting in different types of latency that are more or less susceptible to reactivation. I have found that exposure of neurons to type I interferon (IFN) results in the formation of repressive PML- nuclear bodies, as well as a more restricted form of latency than that established in the absence of type I IFN. Therefore, in Aim 2 of this proposal, I will investigate how PML-nuclear bodies form in response to type I IFN and examine the contribution of PML-nuclear bodies in compacting latent HSV-1 genomes and making them refractory to reactivation. The ultimate goal of these aims is to understand how to preserve long-term HSV-1 latency through either maintaining ATRX association with viral genomes and/or promoting compaction of HSV- 1 genomes in repressive PML-nuclear bodies.

项目总结/文摘