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

• 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
• 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' 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

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。已证实的治疗方法仅限于少数几种病毒，即使存在治疗方法(例如阿昔洛韦 对于单纯疱疹病毒性脑炎)，伤残和死亡仍然很重要。我们对病毒性中枢神经系统感染的了解， 尤其是涉及脊髓的那些，是有限的，并成为阻碍小说发展的障碍 对这些毁灭性疾病的治疗。肠道病毒是病毒诱导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道病毒中最臭名昭著的成员。然而，几个非 包括EV-D68在内的脊髓灰质炎人类肠道病毒(NPEV)也针对中枢神经系统。NPEV很常见，导致 据估计，仅在美国每年就有1000-1500万有症状的感染病例。尽管这些感染中的大多数 不会导致中枢神经系统疾病，这些病毒可以获得神经毒力的能力。最近，猪流感的大规模爆发 世界各地都出现了与神经系统疾病有关的NPEV，这些病毒是 被指定为“重新出现的病原体”。例如，2014年，美国经历了一场急性肺炎疫情 此前罕见的肠道病毒D68(EV-68)在全国范围内暴发期间，儿童出现松驰性脊髓炎(AFM)病例 D68)呼吸道疾病。大约50%的AFM患者呼吸道分泌物中有EV-D68。然而， 在任何患者的脑脊液中都没有检测到EV-D68，这阻止了病原体的建立 EV-D68和AFM之间的联系。我们最近展示了许多(包括IL/52和MO/47)，但不是全部 (如CA4231)，2014年暴发的EV-D68临床分离株可引起新生小鼠神经系统疾病 并建议使用这一新的病毒诱导的中枢神经系统疾病模型来确定EV-EV的模式和机制。 D68致瘫痪。利用嵌合病毒，我们已经证明了5‘非翻译区(UTR) 而病毒结构蛋白VP3和VP1是麻痹的决定因素。在拟议的研究中，我们将使用 确定哪些病毒序列与瘫痪的具体机制有关的类似方法包括 神经细胞感染性和细胞凋亡率。对EV-EV致病机制的了解增加- D68诱导的CNS疾病将为EV-D68诱导的AFM的抗病毒药物的开发提供信息。此外，由 将我们的努力集中在宿主对EV-D68感染的反应上，我们的实验可能会找到治疗方法 对其他电动汽车具有广泛适用性的战略。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。