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：
10225583
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：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225583
关键词：
Acyclovir Animal Model Apoptotic Brain 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 Outcome Disease Progression Encephalitis Enterovirus Enterovirus 68 Epidemic Growth Herpes encephalitis Human Human poliovirus Immune Immune system Individual Infection Interferons Knowledge Link Lung diseases Meningitis Modeling Monitor Morbidity - disease rate Motor Neurons Myelitis Nerve Degeneration Neuraxis Neurologic 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 Therapeutic Time Tropism United States Viral Virus Virus Diseases acute flaccid myelitis central nervous system injury disability effective therapy efficacy evaluation emerging pathogen experience human disease improved improved outcome in vivo Model mortality mouse model neonatal infection neonatal mice nervous system disorder neuroinflammation neuron loss neurotropic neurovirulence new therapeutic target novel prevent respiratory response therapeutic target tissue injury 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; (ii) delineate pathogenic mechanisms that are triggered in the CNS following EV-D68 infection; and (iii) 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 may also have relevance non-viral causes of CNS disease, including neurodegeneration

中枢神经系统（CNS）的病毒感染是发病率和死亡率的重要原因全世界。经过验证的治疗仅限于几种病毒，即使存在治疗（例如，阿西克罗维尔）对于疱疹，单纯脑炎）残疾和死亡仍然很大。我们对病毒中枢神经系统感染的了解，尤其是涉及脊髓的人，受到限制，是反对新颖的发展的障碍这些毁灭性疾病的治疗方法。肠病毒是病毒诱导的中枢神经系统的重要原因感染。尽管脊髓灰质炎病毒（PV）可能是最著名的神经营养性肠病毒，但有几个非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，骨髓炎和脑膜炎。非Polio EV是常见的，估计估计有10-15万仅在美国，有症状的年感染。尽管大多数这些感染不会导致中枢神经系统疾病来自我们自己和其他人的数据表明，这些病毒可以获得神经病毒的能力。最近多年的肠病毒爆发发生了大规模爆发，并且神经性肠病毒已经发生被认为是“重新出现的病原体”。 2014年，美国经历了急性松弛脊髓炎的流行病（AFM）在全国范围内遭受以前罕见的肠病毒D68（EV-D68）呼吸道的儿童病例疾病。大约50％的AFM患者通过RT-PCR在呼吸道分泌中检测到EV-D68，尽管在任何患者的脑脊液中未检测到EV-D68，但阻止了建立 EV-D68和AFM之间的因果关系。我们最近表明，EV-D68的临床分离株来自 2014年爆发引起新生小鼠的神经疾病，并提出使用这种新型病毒诱导的模型中枢神经系统疾病；（i）提高我们对EV-D68诱导的中枢神经系统疾病的理解并研究病毒进化成为神经病毒；（ii）在中枢神经系统中触发的病原机制的描述 EV-D68感染；（iii）评估EV-D68诱导的中枢神经系统疾病的潜在治疗靶标。我们的具有病毒引起的中枢神经系统疾病的其他动物模型的经验将使我们能够迅速确定是否是否 EV-D68发病机理涉及的机制对于感染了中枢神经系统的其他病毒是常见的对EV-D68诱导的中枢神经系统疾病有效的治疗具有广泛的适用性病毒引起的中枢神经系统疾病。我们的结果可能还可能引起中枢神经系统疾病的非病毒原因神经变性