Vaccine Safety: Pathogenesis of virus vaccine neurotoxi

疫苗安全性：病毒疫苗神经毒性的发病机制

• 批准号: 6678771
• 负责人: K. M CARBONE
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6678771
• 关键词: autism; bioassay; biomarker; biotechnology; communicable disease control; developmental neurobiology; disease /disorder model; disease /disorder proneness /risk; drug screening /evaluation; gene expression; host organism interaction; iatrogenic disease; immunoregulation; laboratory rat; method development; model design /development; mumps; neurogenetics; neurotoxicology; neurotoxins; neurotropic virus; polymerase chain reaction; vaccine development; viral vaccines; virulence; virus infection mechanism

Summary: In addition to published articles listed below, manuscripts are submitted or in preparation for: a) Influenza virus neurotoxicity in humans correlates with in vivo replication and spread in neonatal rat brain. b) Vaccinia virus smallpox vaccine neurotoxicity can be identified with a newborn mouse assay using endpoints of day of death and percent survival. Vaccinia virus replicates persistently in the brain of surviving mice until anti vaccinia antibody rises in serum. c) Identification of mumps genomic changes associated with differences in neurovirulence have been identified on the N, P, M, F, HN and L genes. d) Identification of host brain responses to neurovirulent mumps virus strains: Molecular Markers of Neurotoxicity: We have identified mumps virus-related perturbations in CNS gene expression by standard semiquantitative RT-PCR and by differential display techniques, including endogenous immune mediators of the CNS. We have recovered un-characterized gene products from new genes that are altered by virus infection of the brain. We used RNase protection assay to compare changes in endogenous immune mediators in the CNS in animals infected with low and high neurotoxic strains of mumps virus, and demonstrated differences in cytokine expression that correlate with known neurotoxicity. e) Animal Models of CNS Diseases Following Childhood Virus Infection: Autism. Viruses are known etiologic agents of autism (e.g., rubella). Therefore, concerns are raised regarding a possible relationship between childhood vaccines and autism. Because no valid animal models existed to study the pathogenesis of the neuroanatomical and behavioral signs of autism, we developed a rat model of autism using neonatal infection with neurotropic viruse, Borna disease virus. We have characterized autistic-like changes in neuroanatomy, neurochemistry, neurological disease and behavior in these rats. In addition, we have identified regional and developmental changes in neurotransmitters, including serotonin and norepinephrine. A developmental study of damage to developing brain (e.g., cerebellum)in virus infected rats was performed demonstrating anatomical, behavioral and neurological consequences. We have now identified host genetic background features that affect neurotoxic outcomes.We have identified genomic changes in the G and L proteins associated with changes in neurotoxicity outcomes. f) We have begun establishing a mouse neurotoxicity assay for measles virus using mice transgenic for the human measles receptor, CD 46.

摘要：除了下面列出的已发表文章外，还提交了手稿或正在准备： a）流感病毒在人类中的神经毒性与新生大鼠脑中的体内复制和传播相关。 B）牛痘病毒天花疫苗的神经毒性可以用新生小鼠试验使用死亡天数和存活百分比的终点来鉴定。 牛痘病毒在存活小鼠的脑中持续复制，直到血清中出现抗牛痘抗体。 c）已在N、P、M、F、HN和L基因上确定了与神经毒力差异相关的腮腺炎基因组变化。 d）鉴定宿主脑对神经毒性腮腺炎病毒株的反应：神经毒性的分子标志物：我们通过标准半定量RT-PCR和差异显示技术鉴定了CNS基因表达中与腮腺炎病毒相关的扰动，包括CNS的内源性免疫介质。 我们已经从新基因中恢复了未表征的基因产物，这些新基因因病毒感染大脑而改变。 我们使用RNase保护试验比较了低和高神经毒性腮腺炎病毒株感染动物CNS中内源性免疫介质的变化，并证明了与已知神经毒性相关的细胞因子表达的差异。 e）儿童病毒感染后CNS疾病的动物模型：自闭症。 病毒是自闭症的已知病原体（例如，风疹）。 因此，人们对儿童疫苗和自闭症之间可能存在的关系表示担忧。 由于没有有效的动物模型存在研究自闭症的神经解剖学和行为体征的发病机制，我们开发了一个自闭症的大鼠模型，使用新生儿感染嗜神经胶质瘤，博尔纳病病毒。 我们已经在这些大鼠的神经解剖学、神经化学、神经疾病和行为方面描述了自闭症样变化。 此外，我们已经确定了神经递质的区域和发育变化，包括5-羟色胺和去甲肾上腺素。 对发育中大脑损伤的发育研究（例如，小脑）的解剖学、行为学和神经学结果。 我们现在已经确定了影响神经毒性结果的宿主遗传背景特征。我们已经确定了与神经毒性结果变化相关的G和L蛋白基因组变化。 f）我们已经开始使用人麻疹受体CD 46转基因小鼠建立麻疹病毒的小鼠神经毒性试验。