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。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，一些非 脊髓灰质炎人类肠道病毒 (NPEV)，包括 EV-D68，也以中枢神经系统为目标。 NPEV 很常见，导致 据估计，仅在美国每年就有 10-1500 万有症状的感染者。尽管大多数这些感染都 虽然不会导致中枢神经系统疾病，但这些病毒可以获得神经毒力的能力。近期，大面积爆发 NPEV 在世界范围内发生，与神经系统疾病相关，这些病毒 被指定为“重新出现的病原体”。例如，2014年，美国爆发了严重的新冠肺炎疫情。 此前罕见的肠道病毒 D68（EV- D68) 呼吸道疾病。大约 50% 的 AFM 患者呼吸道分泌物中含有 EV-D68。然而， 在任何患者的脑脊液中均未检测到 EV-D68，从而防止了致病原因的建立 EV-D68 和 AFM 之间的链接。我们最近表明许多（包括 IL/52 和 MO/47），但不是全部 （如 CA4231），2014 年爆发的 EV-D68 临床分离株可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中枢神经系统疾病的新模型来定义EV-的模式和机制 D68 引起的麻痹。使用嵌合病毒，我们已经证明 5' 非翻译区 (UTR) 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 确定哪些病毒序列参与特定麻痹机制的类似方法，包括 神经元感染和细胞凋亡。增加对 EV 致病机制的了解 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，通过 将我们的努力集中在宿主对 EV-D68 感染的反应上，我们的实验可能会确定治疗方法 对其他电动汽车具有广泛适用性的策略。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。