A surface-exposed region of the UL37 protein that is essential for alphaherpesvirus neuroinvasion

UL37 蛋白的表面暴露区域对于 α 疱疹病毒神经侵袭至关重要

• 批准号: 9198838
• 负责人: Alexsia L Richards
• 金额: $ 5.43万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198838
• 关键词: Address; Advanced Development; Afferent Neurons; Affinity; Antiviral Agents; Attenuated; Attenuated Live Virus Vaccine; Axon; Axonal Transport; Blindness; Brain; Capsid; Cell Line; Cell Nucleus; Cells; Codon Nucleotides; Complex; Cornea; Data; Defect; Dependence; Developed Countries; Development; Dynein ATPase; Encephalitis; Epithelial Cells; Exhibits; Eye; Generations; Herpesviridae; Herpesvirus 1; High Prevalence; Human; Immune response; Immunocompetent; Infection; Infection prevention; Invaded; Kinetics; Knowledge; Life; Microtubules; Modeling; Molecular; Morbidity - disease rate; Mothers; Motion; Motor; Mus; Mutagenesis; Mutate; Mutation; Nature; Nervous system structure; Neuraxis; Neurons; Newborn Infant; Peripheral; Peripheral Nervous System; Phenotype; Plant Resins; Play; Population; Property; Protein Isoforms; Proteins; Rattus; Research; Resources; Rodent; Role; Sensory; Sepharose; Simplexvirus; Suid Herpesvirus 1; Surface; Testing; Trigeminal Nuclei; Tropism; Universities; Varicellovirus; Viral; Viral Genome; Virion; Virulence; Virulence Factors; Virulent; Virus; base; dynactin; experience; follow-up; in vivo; latent infection; member; mortality; mutant; neuronal cell body; pathogen; post-doctoral training; prevent; public health relevance; relating to nervous system; research study; retrograde transport; trait; transmission process

 DESCRIPTION (provided by applicant): Alphaherpesviruses are pathogens that proficiently invade the nervous system of an immunocompetent host. Spread of these neuroinvasive herpesviruses from sensory neurons to the eye, brain or from mother to newborn, are significant causes of morbidity and mortality. Herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV) are representative members of the two genuses of mammalian neuroinvasive herpesviruses (simplexviruses & varicelloviruses). These viruses rely on spread to the nervous system to establish life-long latent infections, yet very little is known regarding the molecular mechanisms that underlie this remarkable trait. The UL37 protein is a conserved structural component of the alphaherpesvirus virion. Our lab recently identified three highly conserved surface-exposed regions in the amino terminal half of this protein. As part of my preliminary data for this proposal I demonstrated that pseudorabies virus (PRV) mutated in one of these regions, designated R2, replicates to near wild-type titers in epithelial cells, however fails to invade the host nervous system due to a defect in sustained retrograde transport within the axon. This proposal is founded on the hypothesis that UL37 performs critical effector functions that are required during neural delivery. The experiments proposed will examine the mechanism by which this mutant is defective at long distance axon transport as well as determine if the effector functions of the R2 region are conserved in the human pathogen, HSV-1. The R2 mutant has the capacity to generate a robust immune response due to its replication in peripheral cells. This property in combination with the loss in neuroinvasive capabilities makes the R2 mutant uniquely suited to advance the development of live-attenuated vaccines against both human and veterinary alphaherpesvirus infection by preventing latency establishment.

 描述（由适用提供）：αHerpesviruses是病原体，深深地侵入免疫能力宿主的神经系统。这些神经侵袭性疱疹病毒从感觉神经元到眼睛，大脑或从母亲到新生儿的传播是发病率和死亡的重大原因。单纯疱疹病毒1型（HSV-1）和伪标记病毒（PRV）是哺乳动物神经侵袭性疱疹病毒（单纯毒病毒和vericellovires）的两个属的代表成员。这些病毒依靠传播到神经系统来建立终身的潜在感染，但对于基于这种非凡特征的分子机制而言，知之甚少。 UL37蛋白是α-鞘病毒病毒病毒的保守结构成分。我们的实验室最近确定了该蛋白质的氨基末端中三个高度保守的表面暴露区域。作为我该提案初步数据的一部分，我证明了在其中一个区域中突变（指定R2）在上皮细胞中复制到接近野生型滴度的伪标记病毒（PRV），但是未能侵入 由于轴突内持续逆行运输的缺陷，宿主神经系统。该提案建立在以下假设的基础上：UL37执行神经传递过程中需要的关键效应子功能。提出的实验将检查该突变体在长距离轴突传输处有缺陷的机制，并确定效应器是否存在 R2区域的功能在人类病原体HSV-1中保守。 R2突变体的能力由于其在外围细胞中的复制而产生可靠的免疫响应。这种特性与神经侵染能力的损失相结合，使R2突变体独特地适合于通过防止潜伏期建立来推动针对人类和兽医alphaherpesvirus感染的生命衰减疫苗的开发。