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 国际吧抗病毒治疗仅限于少数几种病毒，即使存在治疗方法（如阿昔洛韦）， 单纯疱疹病毒性脑炎）的残疾和死亡率仍然很高。我们对病毒性中枢神经系统感染的了解， 特别是涉及脊髓的那些，是有限的，并作为一个障碍，对新的发展， 这些毁灭性疾病的治疗方法。肠道病毒是引起病毒性中枢神经系统疾病的重要原因 感染.虽然脊髓灰质炎病毒（PV）可能是最知名的神经营养性肠道病毒，但几种 非脊髓灰质炎人类EV也靶向CNS，并导致许多临床表现，包括 脑炎、脑炎和脑膜炎。非脊髓灰质炎EV很常见，估计造成1000 - 1500万或更多 每年仅在美国就有症状的感染。虽然这些感染中的大多数不会导致CNS疾病 来自我们和其他人的数据表明，这些病毒可以获得神经毒性的能力。近几 近年来，肠道病毒在世界范围内发生了大规模爆发，嗜神经性肠道病毒已被 被认为是“重新出现的病原体”2014年，美国发生急性弛缓性肌麻痹症疫情 (AFM)在此前罕见的肠道病毒D 68（EV-D 68）呼吸道疾病全国爆发期间， 疾病大约50%的AFM患者在呼吸道分泌物中通过RT-PCR检测到EV-D 68， 尽管在任何患者的脑脊液中均未检测到EV-D 68，但这阻止了 EV-D 68和AFM之间的因果关系。我们最近已经表明，临床分离的EV-D 68从 2014年爆发导致新生小鼠神经系统疾病，并建议使用这种病毒诱导的新模型 CNS疾病;（i）增加我们对EV-D 68诱导的CNS疾病的理解，并研究病毒如何 进化成为神经毒性（目标1）;（ii）描述在CNS中触发的致病机制 在EV-D 68感染后（目的3），和（iv）评估EV-D 68诱导的CNS的潜在治疗靶点 疾病我们在病毒诱导的CNS疾病的其他动物模型方面的经验将使我们能够快速鉴定 EV-D 68致病机制是否与其他感染CNS的病毒相同， 有效对抗EV-D 68诱导的CNS疾病的治疗是否具有广谱 适用于其他病毒引起的CNS疾病。我们的研究结果也有望与非病毒相关 CNS疾病的原因，包括神经变性