EV-D68-induced CNS disease: pathogenic mechanisms and identification of therapeutic targets.

EV-D68诱导的中枢神经系统疾病：致病机制和治疗靶点的鉴定。

基本信息

批准号：
9436831
负责人：
Kenneth L. Tyler
金额：
$ 34.02万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9436831
关键词：
Acute Acyclovir Animal Model Antiviral Agents Brain CASP3 gene Cell Death Cell Survival Cells Central Nervous System Diseases Central Nervous System Infections Central Nervous System Viral Diseases Cerebrospinal Fluid Cessation of life Child Clinical Data Development Disease Disease Marker Disease Outbreaks Disease Progression Employee Strikes Encephalitis Enterovirus Enterovirus 68 Epidemic Evaluation Growth Herpes encephalitis Human Human poliovirus Immune Immune response Immune system Individual Infection Interferons Intravenous Immunoglobulins Knowledge Link Lung diseases Meningitis Modeling Monitor Morbidity - disease rate Motor Neurons Mus Myelitis Neonatal Nerve Degeneration Neuraxis Neurologic Neuronal Injury Neuropathogenesis Paralysed Pathogenesis Pathogenicity Patients Peripheral Peripheral Nervous System Poliomyelitis Reverse Transcriptase Polymerase Chain Reaction Site Slice Spinal Cord Spinal Cord Diseases Spinal cord injury Testing Time Tissues Tropism United States Viral Virus Virus Diseases central nervous system injury disability effective therapy experience human disease improved outcome in vivo Model mortality mouse model nervous system disorder neuron loss neurotropic neurovirulence new therapeutic target novel pathogen prevent respiratory response therapeutic target treatment strategy

项目摘要

Virus infections of the central nervous system (CNS) are a significant cause of morbidity and mortality worldwide. Proven treatments are limited to only a few viruses and even when treatments exist (e.g. acyclovir for herpes simplex encephalitis) disability and death remain significant. Our knowledge of viral CNS infections, particularly those involving the spinal cord, is limited and serves as a barrier against the development of novel treatments for these devastating diseases. Enteroviruses are an important cause of virus-induced CNS infections. Although poliovirus (PV), is perhaps the most well-known of the neurotrophic enteroviruses, several non-polio human EVs also target the CNS and are responsible for numerous clinical manifestations, including encephalitis, myelitis and meningitis. Non-polio EVs are common, causing an estimated 10–15 million or more symptomatic annual infections in the US alone. Though most of these infections do not result in CNS disease data from ourselves and others suggest that these viruses can acquire the ability to be neurovirulent. In recent years large outbreaks of enteroviruses have occurred worldwide and neurotropic enteroviruses have been deemed “re-emerging pathogens”. In 2014, the United States experienced an epidemic of acute flaccid myelitis (AFM) cases in children during a nationwide outbreak of previously rare enterovirus D68 (EV-D68) respiratory disease. Approximately 50% of AFM patients had EV-D68 detected by RT-PCR in respiratory secretions, although EV-D68 was not detected in cerebrospinal fluid from any patient, preventing the establishment of a causative link between EV-D68 and AFM. We have recently shown that clinical isolates of EV-D68 from the 2014 outbreak cause neurologic disease in neonatal mice and propose to use this novel model of virus-induced CNS disease to; (i) increase our understanding of EV-D68-induced CNS disease and investigate how viruses evolve to become neurovirulent (Aim 1); (ii) delineate pathogenic mechanisms that are triggered in the CNS following EV-D68 infection (Aim 3), and (iv) evaluate potential therapeutic targets for EV-D68 induced CNS disease. Our experience with other animal models of virus-induced CNS disease will allow us to rapidly identify whether mechanisms involved in EV-D68 pathogenesis are common to other viruses that infect the CNS and whether treatments which are effective against EV-D68-induced CNS disease have broad spectrum applicability to other virus-induced CNS diseases. Our results are also expected to have relevance non-viral causes of CNS disease, including neurodegeneration

中心神经系统（CNS）的病毒感染是病态和荒谬的重要原因在全球范围内。对于疱疹单纯脑炎）残疾和死亡死亡remean含义。特别是刺脊髓毁灭性疾病的治疗感染。易体病毒（PV），也许是最著名的神经营养病毒。非Polio人类电动汽车也针对中枢神经系统，并负责许多临床表现，包括脑炎，脊髓炎和脑膜炎是常见的仅美国的年度感染。来自我们自己和其他人的数据表明，您可以获得最近的神经性的能力。多年发生的大量肠病毒发生了全球神经肝病病毒的发生美国被认为是“重新发育的病原体”。（AFM）在全国范围内的儿童库斯（Causs）疾病。尽管在大脑液体流体流体中未检测到EV-D68，任何患者都无法建立 EV-D68和AFM之间的因果关系。 2014年对新生儿小鼠的神经系统疾病的态度，并建议使用这种病毒诱导的这种模型 CNS疾病（i）增加了我们对EV-D68诱导的中枢神经系统疾病的理解进化成为神经毒动（AIM 1）； EV-D68感染后（AIM 3），（IV）评估EV-D68诱导的CNS的潜在治疗靶标疾病。 EV-D68发病机理中涉及的机制是否在其他病毒中常见针对EV-D68诱导的中枢神经系统疾病有效的治疗是否具有广泛的范围适用于其他病毒引起的CNS疾病。中枢神经系统疾病的原因，包括神经变性