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。

• 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
• 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

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

中枢神经系统（CNS）的病毒感染是发病和死亡的重要原因 全世界。经证实的治疗方法仅限于少数病毒，即使存在治疗方法（例如阿昔洛韦） 单纯疱疹脑炎）残疾和死亡仍然很严重。我们对病毒性中枢神经系统感染的了解， 特别是那些涉及脊髓的，是有限的，并成为新的开发的障碍 治疗这些毁灭性的疾病。肠道病毒是病毒诱发中枢神经系统疾病的重要原因 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道病毒，但有几种 非脊髓灰质炎人类 EV 也以中枢神经系统为目标，并导致许多临床表现，包括 脑炎、脊髓炎和脑膜炎。非脊髓灰质炎电动汽车很常见，估计造成 10-1500 万或更多 仅在美国，每年都会出现有症状的感染。尽管大多数感染不会导致中枢神经系统疾病 我们自己和其他人的数据表明，这些病毒可以获得神经毒性的能力。近来 多年来，全球范围内发生了肠道病毒的大规模爆发，嗜神经性肠道病毒已被 被视为“重新出现的病原体”。 2014年，美国爆发了急性弛缓性脊髓炎疫情 (AFM) 全国范围内爆发以前罕见的肠道病毒 D68 (EV-D68) 呼吸道疾病期间发生的儿童病例 疾病。大约 50% 的 AFM 患者通过 RT-PCR 在呼吸道分泌物中检测到 EV-D68， 尽管在任何患者的脑脊液中均未检测到 EV-D68，但仍无法建立 EV-D68 和 AFM 之间存在因果关系。我们最近表明，EV-D68 的临床分离株来自 2014年的爆发导致新生小鼠出现神经系统疾病，并建议使用这种病毒诱导的新型模型 中枢神经系统疾病； (i) 增加我们对 EV-D68 诱导的中枢神经系统疾病的了解并研究病毒如何 进化为具有神经毒性（目标 1）； (ii) 描述中枢神经系统中触发的致病机制 EV-D68 感染后（目标 3），以及 (iv) 评估 EV-D68 诱导的 CNS 的潜在治疗靶点 疾病。我们在其他病毒引起的中枢神经系统疾病动物模型方面的经验将使我们能够快速识别 EV-D68 发病机制是否与其他感染中枢神经系统的病毒相同？ 对 EV-D68 引起的中枢神经系统疾病有效的治疗是否具有广谱性 适用于其他病毒引起的中枢神经系统疾病。我们的结果预计也具有非病毒相关性 中枢神经系统疾病的原因，包括神经变性