Neurovirulence determinants of neonatal HSV disease

项目概要 该提案描述了独立研究职业发展的五年培训计划 重点关注决定儿童大脑对感染的易感性的病毒与宿主的相互作用。具体来说， 申请人致力于阐明病毒遗传变异如何影响神经毒力，既通过改变病毒 功能并诱导免疫逃逸。申请人是该医院的传染病主治医师 费城儿童医院 (CHOP) 曾接受过基础神经免疫学博士学位培训。目标 该奖项的目的是培养和完善作为一名成功的职业生涯所需的基本技能 独立研究者，包括大型遗传数据测序和生物信息分析方面的专业知识 集、病毒基因组编辑以及神经相关的病毒感染体外和体内模型。导师们 获得该奖项的包括国际公认的病毒宿主领域的领军人物 Matthew Weitzman 博士 相互作用，以及丹尼斯·科尔森博士（Dennis Kolson），一位医师科学家和神经毒力机制专家。添加 为了对申请人的科学职业指导的深度和广度，科学咨询委员会是 由来自不同且互补领域的科学家和医师科学家组成。阿赫塔尔博士还将 受益于 CHOP 和大学提供的无与伦比的资源和指导 宾夕法尼亚州。 拟议的研究重点是病毒遗传变异在确定临床表现中的作用 新生儿单纯疱疹病毒 (HSV) 疾病，特别是感染新生儿大脑的能力。单纯疱疹病毒 新生儿脑部感染会导致严重脑炎和永久性神经功能缺损，但因素 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 HSV 基因组内存在遗传变异，但尚未评估这些变异如何影响病毒生长 特征或人类疾病的表现。成功完成拟议的研究将确定 HSV 遗传变异与新生儿中枢神经系统疾病相关，决定了它们对病毒传播的影响 神经元及其改变中枢神经系统感染进展的能力。这将通过大规模病毒式传播来实现 基因组测序以确定与中枢神经系统疾病最常见的变异，然后进行创建 突变病毒，以确定已识别的变异对病毒在病毒之间传播的个体影响 体外室测定的简化神经元连接以及小鼠的复杂神经元回路 视网膜。本提案中概述的研究将首次深入了解新生儿的变化如何 HSV 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.