Genomic and molecular determinants of EV-D68 neuroinvasive disease

EV-D68神经侵袭性疾病的基因组和分子决定因素

基本信息

批准号：
10657198
负责人：
Kenneth L. Tyler
金额：
$ 38.88万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657198
关键词：
5&apos Untranslated Regions Acyclovir Age Antiviral Agents Apoptosis Brain Central Nervous System Central Nervous System Diseases Central Nervous System Infections Central Nervous System Viral Diseases Cerebrospinal Fluid Cerebrum Cessation of life Child Clinical Communities Dependence Development Disease Disease Outbreaks Enterovirus Enterovirus 68 Epidemic Experimental Models Genetic Genomics Herpes encephalitis Human Human poliovirus Immune response Immunodeficient Mouse In Vitro Incidence Induction of Apoptosis Infection Innate Immune Response Interferons Intramuscular Injections Knowledge Link Methods Modeling Molecular Morbidity - disease rate Motor Neurons Mus Mutation Nature Neurons Paralysed Pathogenesis Pathogenicity Patients Pattern Peripheral Pharmacologic Substance Poliomyelitis Proteins Recovery Research Personnel Respiratory Disease Role Sensory Signal Transduction Slice Spinal Cord Spinal cord injury Testing Therapeutic Therapeutic Intervention Time United States Viral Viral Pathogenesis Viral Structural Proteins Virulence Factors Virus Virus Diseases acute flaccid myelitis age related antiviral drug development disability emerging pathogen epidemiology study experience experimental study human disease improved in vitro Model in vivo induced pluripotent stem cell innovation juvenile animal member mortality mouse model neonatal infection neonatal mice nervous system disorder neurovirulence novel pathogenic virus prevent previous outbreak respiratory response retrograde transport

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. Poliovirus is the most infamous member of the neurotrophic enteroviruses. However, several non- polio human enteroviruses (NPEVs), including EV-D68, also target the CNS. NPEVs are common, causing an estimated 10–15 million symptomatic annual infections in the US alone. Although most of these infections do not result in CNS disease, these viruses can acquire the ability to be neuro-virulent. Recently, large outbreaks of NPEVs have occurred worldwide that have been associated with neurologic disease and these viruses are designated “re-emerging pathogens”. For example, 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 in respiratory secretions. However, EV-D68 was not detected in the cerebrospinal fluid of any patient, preventing the establishment of a causative link between EV-D68 and AFM. We have recently shown that many (including IL/52 and MO/47), but not all (such as CA4231), 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 define patterns and mechanisms of EV- D68-induced paralysis. Using chimeric viruses we have demonstrated that the 5’ untranslated region (UTR) and the viral structural proteins VP3 and VP1 are determinants of paralysis. In the proposed studies we will use similar methods to determine which viral sequences are involved in specific mechanisms of paralysis, including neuronal infectivity and apoptosis. An increased knowledge of pathogenic mechanisms that are involved in EV- D68-induced CNS disease will inform the development of antivirals for EV-D68-induced AFM. In addition, by focusing our efforts on host responses to EV-D68 infections our experiments may identify therapeutic strategies that have broad spectrum applicability to additional EVs. Our studies may also have relevance for other viral and non-viral causes of CNS disease.

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。脊髓灰质炎病毒是神经营养性肠病毒中最臭名昭著的成员。但是，几个非 - 脊髓灰质炎人肠病毒（NPEV），包括EV-D68，也针对CNS。 NPEV很常见，导致仅在美国，估计有10-15万症状的年度感染。尽管大多数这些感染都这些病毒不会导致CNS疾病，可以获得成为神经病毒的能力。最近，大暴发 NPEV已在全球范围内与神经系统疾病有关，这些病毒是指定的“重新出现病原体”。例如，2014年，美国经历了急性流行在全国范围内罕见的肠病毒D68爆发期间，儿童的脊髓炎（AFM）病例（AFM）病例（EV- D68）呼吸道疾病。大约50％的AFM患者在呼吸道分泌中持有EV-D68。然而，在任何患者的脑脊液中未检测到EV-D68，以阻止建立病因 EV-D68和AFM之间的链接。我们最近显示了许多（包括IL/52和MO/47），但不是全部（例如CA4231），2014年爆发中EV-D68的临床分离株引起新生儿小鼠的神经系统疾病并提出使用这种新型病毒诱导的中枢神经系统疾病模型来定义EV-的模式和机制 D68诱导的瘫痪。使用嵌合病毒，我们已经证明了5'未翻译区域（UTR）病毒结构蛋白VP3和VP1由麻痹确定。在拟议的研究中，我们将使用类似的方法来确定哪些病毒序列参与瘫痪的特定机制，包括神经元感染和凋亡。对EV-涉及的致病机制的知识越来越多 D68诱导的中枢神经系统疾病将为EV-D68诱导的AFM的抗病毒药发育提供信息。另外，由将我们的精力集中在宿主对EV-D68感染的反应上，我们的实验可能会识别治疗具有广泛适用于其他电动汽车的策略。我们的研究也可能与中枢神经系统疾病的其他病毒和非病毒原因。