Neurovirulence determinants of neonatal HSV disease

项目摘要 该提案描述了一项发展独立研究事业的五年培训计划。 专注于病毒与宿主的相互作用，这决定了儿童大脑对感染的易感性。具体来说， 申请者努力阐明病毒遗传变异如何通过改变病毒来影响神经毒力 功能和诱导免疫逃逸。申请人为该院传染病主治医师。 费城儿童医院(CHOP)，之前接受过基础神经免疫学博士培训。目标 这一奖项的目的是发展和完善成功的职业生涯所需的基本技能 独立调查员，包括大量遗传数据的测序和生物信息学分析方面的专业知识 套装，病毒基因组编辑，以及与神经学相关的病毒感染的体外和体内模型。导师们 该奖项的获奖者包括国际公认的病毒宿主领域的领导者马修·魏茨曼博士 和丹尼斯·科尔森博士，他是一位内科科学家和神经毒性机制方面的专家。要添加 对申请者进行科学职业指导的深度和广度，科学咨询委员会是 由来自不同和互补领域的科学家和内科科学家组成。阿赫塔尔博士还将 受益于CHOP和芝加哥大学提供的无与伦比的资源和指导 宾夕法尼亚州。 建议的研究集中在病毒遗传变异性在决定临床表现中的作用。 新生儿单纯疱疹病毒(HSV)疾病的风险，特别是感染新生儿大脑的能力。单纯疱疹病毒 新生儿脑感染会导致严重的脑炎和永久性的神经功能障碍，但这些因素 促进中枢神经系统(CNS)感染的因素尚不清楚。最近的研究表明，大量的 HSV基因组中存在遗传变异，但尚未评估这些变异如何影响病毒生长 人类疾病的特征或表现。成功完成拟议的研究将确定 与新生儿中枢神经系统疾病相关的HSV基因变异，决定了它们对病毒传播的影响 神经元，以及它们改变中枢神经系统感染进展的能力。这将通过大规模的病毒 基因组测序以确定最常见的与中枢神经系统疾病相关的变异，然后创建 以确定已识别的变异对病毒之间传播的个体影响 体外小室分析的简化神经元连接和小鼠复杂的神经元回路 视网膜。这项提案中概述的研究将提供对新生儿如何变化的首次洞察 单纯疱疹病毒基因组影响神经毒力和中枢神经系统疾病的发展。

Project Summary This proposal describes a five-year training plan for the development of an independent research career focused on the virus-host interactions that dictate susceptibility of the pediatric brain to infection. Specifically, the applicant strives to elucidate how viral genetic variation influences neurovirulence, both by altering viral function and inducing immune escape. The applicant is an attending Infectious Diseases physician at the Children's Hospital of Philadelphia (CHOP) with previous PhD training in basic neuroimmunology. The goals for this award are to develop and refine the essential skills that will be required for a successful career as an independent investigator, including expertise in sequencing and bioinformatic analysis of large genetic data sets, viral genome editing, and neurologically-relevant in vitro and in vivo models of viral infection. The mentors for this award include Dr. Matthew Weitzman, an internationally recognized leader in the field of virus-host interactions, and Dr. Dennis Kolson, a physician-scientist and expert in mechanisms of neurovirulence. To add depth and breadth to the scientific career guidance of the applicant, a scientific advisory committee is composed of scientists and physician-scientists from diverse and complementary fields. Dr. Akhtar will also benefit from the unparalleled resources and mentorship available at both CHOP and the University of Pennsylvania. The proposed research focuses on the role of viral genetic variability in determining the clinical manifestations of neonatal herpes simplex virus (HSV) disease, particularly the ability to infect the neonatal brain. HSV infection of the neonatal brain causes severe encephalitis and permanent neurologic deficits, but the factors that promote central nervous system (CNS) infection are not known. Recent studies show that substantial genetic variability exists within HSV genomes, but have not evaluated how these variations impact viral growth characteristics or human disease manifestations. Successful completion of the studies proposed will identify HSV genetic variations associated with neonatal CNS disease, determine their impact on viral spread between neurons, and their ability to alter progression to CNS infection. This will be accomplished by large-scale viral genomic sequencing to identify variations most frequently associated with CNS disease, followed by creation of mutant viruses to determine the individual impact of identified variations on viral spread between the simplified neuronal connections of in vitro chamber assays, and the complex neuronal circuits of the murine retina. The studies outlined in this proposal will provide the first insights into how variations in the neonatal HSV genome impact neurovirulence and the development of CNS disease.