Dissecting the Contribution of Viral Genetic Variation to HSV-1 Neuropathogenesis

单纯疱疹病毒(HSV)感染会导致反复发生的唇疱疹、角膜病变、生殖器溃疡和 在极少数情况下，脑炎。HSV-1毒株的致病机理不同，在急性感染中表现出变异， 动物模型中的潜伏期和重新激活。McKrae分离株是已知的最强毒力的HSV-1之一 菌株，并以比其他菌株更高的频率重新激活。相比之下，菌株KOS，这是 通常用于研究HSV-1基因的功能和发病机制，其神经侵袭性和毒性比 其他许多HSV-1毒株在动物模型中的感染。大量报告表明，有几个基因 ICP0和ICP34.5在单纯疱疹病毒的神经致病和毒力中起着关键作用。然而，特定的病毒 调节McKrae、Kos和其他HSV-1病理表型的基因和遗传变异 菌株在很大程度上是未知的。了解驱动神经发病机制的分子机制 HSV-1在控制疱疹感染及其引起的疾病方面至关重要。我们最近编目了 通过基因组测序，Kos和McKrae之间的大部分等位基因差异，识别出1,203个 单核苷酸多态(SNPs)和插入/缺失事件区分菌株。因此，我们是 在一个独特的位置来解决导致致病性差异的多态子集 在科斯和麦克雷之间。我们的工作将为未来的功能性、机械性表征提供一个平台 致病基因座上的等位基因变异。 这项应用的目的是确定HSV-1基因组中起作用的基因座。 单纯疱疹病毒1型McKrae株比Kos株神经侵袭性和致病作用更强。对大多数人来说 该提案有效地实现了这一目标，将三个具有不同专业知识的实验室聚集在一起 将是这个项目成功的关键。 在这种背景下，我们提出的问题是：McKrae基因组的哪些区域起作用 它的神经侵袭性吗？为了解决这个问题，我们生成了基因组数据，并确定了 神经组织中区分Kos和McKrae的特定复制表型，表明McKrae 小鼠的神经发病机制。我们进行这些研究的理由是，全面了解 HSV-1致病机制中的分子事件可能促进新的治疗干预措施的发展 预防或治疗单纯疱疹病毒传播的疾病。提出了以下具体目标： 具体目标1：确定HSV-1基因组中与神经侵袭性相关的区域。 具体目标2：精细作图，并从功能上描述与HSV-1神经侵袭有关的基因座。 在这个项目完成时，我们将确定一组特定的McKrae等位基因，这些等位基因强烈地 与其神经侵袭能力有关。我们的研究结果预计将对我们的 了解HSV-1用于增强其致病机制的机制。

Herpes simplex virus (HSV) infections result in recurrent cold sores, corneal lesions, genital ulcers, and in rare cases, encephalitis. Strains of HSV-1 differ in their pathogenesis and show variation in acute infection, latency, and reactivation in animal models. The McKrae isolate is known to be among the most virulent HSV-1 strains, and also reactivates at a higher frequency than other strains. In contrast, strain KOS, which is commonly used to investigate HSV-1 gene function and pathogenesis, is less neuroinvasive and virulent than many other strains of HSV-1 in animal models of infection. Numerous reports indicate that several genes such as ICP0 and ICP34.5 play pivotal roles in HSV neuropathogenesis and virulence. However, the specific viral genes and genetic variants that modulate the pathological phenotypes of McKrae, KOS, and other HSV-1 strains are largely unknown. Understanding the molecular mechanisms that drive the neuropathogenesis of HSV-1 is critical in controlling herpetic infections and the diseases they cause. We have recently catalogued the majority of the allelic differences between KOS and McKrae via genome sequencing, identifying 1,203 single nucleotide polymorphisms (SNPs) and insertion/deletion events distinguishing the strains. Thus, we are in a unique position to resolve the subset of polymorphisms that lead to the differences in pathogenicity between KOS and McKrae. Our work will provide a platform for future functional, mechanistic characterizations of the allelic variants at the causative loci. The objective of this application is to identify loci within the HSV-1 genome that play a role in the heightened neuroinvasiveness and pathogenesis of the HSV-1 strain McKrae over the strain KOS. To most effectively accomplish this objective, the proposal brings together three laboratories with distinct expertise that will be critical for the success of this project. With this background, the question we are asking is: Which regions of the McKrae genome contribute to its neuroinvasiveness? To address this question we have generated genomic data, and have identified specific replication phenotypes in neural tissues that distinguish KOS and McKrae, demonstrating McKrae’s neuropathogenesis in mice. Our rationale for these studies is that a comprehensive understanding of the molecular events in HSV-1 pathogenesis may facilitate the development of new therapeutic interventions to prevent or treat HSV-mediated diseases. The following specific aims are proposed: Specific Aim 1: Identify regions of the HSV-1 genome linked to neuroinvasiveness. Specific Aim 2: Fine map, and functionally characterize loci contributing to HSV-1 neuroinvasiveness. At the completion of this project, we will identify a set of specific McKrae alleles that are strongly associated with its neuroinvasive capacity. Findings from our research are expected to positively impact our understanding of mechanisms used by HSV-1 to enhance its pathogenesis.