Neuronal Regulation of HSV Lytic and Latent Infection

HSV 溶解和潜伏感染的神经调节

基本信息

批准号：
7905621
负责人：
Nancy M. Sawtell
金额：
$ 14.44万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-12 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7905621
关键词：
Acute Address Afferent Neurons Antiviral Agents Apoptosis Arts Biochemical Biological Blindness Brain Cells Cessation of life Cultured Cells Data Defense Mechanisms Development Disease Encephalitis Environment Event Evolution Explosion Family Fibroblasts Ganglia Gene Transfer Genome Stability Goals HIV Health Human Immediate-Early Proteins In Vitro Individual Infection Inflammatory Interferons Knockout Mice Knowledge Lead Life Lytic Lytic Phase Lytic Virus Maintenance Malignant Neoplasms Mediating Methods Molecular Morbidity - disease rate Mus Myxoid cyst Nervous system structure Neurons Nuclear Oncolytic viruses Outcome Output PML gene Pathogenesis Pathology Physiological Play Population Positioning Attribute Prema Probability Proteins Publishing RNA Interference Regulation Regulatory Pathway Repression Research Role Sensory Ganglia Series Simplexvirus TRIM Family Testing Time Transgenic Animals Tumor Suppression Vaccine Design Vaccines Viral Viral Genes Viral Genome Viral Proteins Viral Vector Virus Virus Diseases Virus Latency Virus-Cell Membrane Interaction Work base cell suicide design gene repression gene transfer vector genital herpes improved in vivo in vivo Model inhibitor/antagonist innovation knowledge base latent infection member mortality mouse model mutant neonate novel novel therapeutics pathogen premature prevent programs public health relevance reactivation from latency research study response stressor transcription factor PML transmission process treatment strategy virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex virus infection is the leading cause of sporadic fatal encephalitis worldwide and infectious blindness in the US. Transmission to the neonate is associated with high morbidity and mortality and an individual with genital HSV infection is 2-3 times more likely to acquire HIV. Once infected, there is currently no way to eliminate the latent viral genome, which persists for the life of the host and periodically reactivates producing infectious viral progeny that then is transmitted to new hosts. Considering that more than 70% of the world's population is currently infected with HSV, the direct and indirect impact of this virus to human health is profound. Despite this importance, our understanding of the viral/host interactions underlying the core aspects HSV pathogenesis in vivo, namely the establishment of and reactivation from latency, remains inadequate to direct the rationale design of preventative and treatment strategies. The long term goal of the proposed research is to understand those interactions between HSV and the nervous system which result in the establishment of latency and subsequent reactivation and the long term associated pathologies. Progress has been made in identifying key viral genes involved regulating latency, but the physiological changes in neurons that subvert or enhance the entry into and exit from latency are not understood. In this proposal we will pursue our important new observations that promyelocytic leukemia protein (PML) and the formation of PML-nuclear bodies (PML-NB) in neurons in vivo plays a central role in the establishment of latency and reactivation. Using state of the art quantitative in vivo methods, specific knock out mice, and HSV mutants we will: (1) Determine the role of PML and PML-NB formation in vivo on HSV: (i) lytic infection, (ii) establishment and maintenance of latent infections, and (iii) exit from latency and reactivation; and (2) Determine the biological significance of PML disruption by ICP0 in vivo: (i) during acute ganglion infection; and (ii) in sensory neurons during reactivation from latency. PUBLIC HEALTH RELEVANCE: We propose to determine the viral/host interactions that govern the establishment and maintenance of herpes simplex virus latency and periodic entry into the lytic replicative cycle. This knowledge will lead directly to improved design of vaccines, gene transfer vectors, oncolytic viruses to treat cancer, and may reveal new anti-viral targets.

描述（由申请人提供）：单纯疱疹病毒感染是全球零星致命性脑炎和美国感染性失明的主要原因。向新生儿的传播与高发病率和死亡率有关，生殖器HSV感染的个体获得HIV的可能性高2-3倍。一旦被感染，目前就无法消除潜在病毒基因组，该基因组一直持续到宿主的生命并定期重新激活产生传染性病毒后代，然后传播给新宿主。考虑到目前有超过70％的世界人口感染了HSV，这种病毒对人类健康的直接和间接影响是深远的。尽管这一点很重要，但我们对核心方面的病毒/宿主相互作用的理解，体内HSV发病机理，即潜伏期的建立和重新激活，仍然不足以指导预防和治疗策略的理由设计。拟议研究的长期目标是了解HSV与神经系统之间的相互作用，从而导致延迟和随后的重新激活以及长期相关的病理。在识别关键病毒基因涉及调节潜伏期的过程中取得了进展，但是尚不清楚颠覆或增强进入潜伏期的神经元的生理变化。在这项提案中，我们将追求重要的新观察结果，即临床细胞性白血病蛋白（PML）和体内神经元中PML - 核体（PML-NB）的形成在建立潜伏期和重新激活中起着核心作用。使用最先进的体内方法，特定的敲除小鼠和HSV突变体，我们将：（1）确定pml和pml-nb在体内在HSV中的作用：（i）裂解感染，（ii）建立和建立和维持潜在感染，（iii）退出潜伏期和重新激活；（2）确定ICP0在体内受到PML破坏的生物学意义：（i）急性神经节感染期间；（ii）在潜伏期重新激活期间的感觉神经元中。公共卫生相关性：我们建议确定控制疱疹病毒潜伏期的建立和维护的病毒/宿主相互作用，并定期进入裂解复制周期。这些知识将直接导致改进的疫苗设计，基因转移载体，肿瘤病毒治疗癌症，并可能揭示新的抗病毒靶标。