Investigation of the impact of viral factors on the severity of chronic HSV-2 infection

项目摘要 人类单纯疱疹病毒2型（HSV-2）是一种性传播病原体，影响5亿人 国际吧HSV-2疾病的大部分全球负担是由于该病毒能够建立慢性感染， 感染，以复发性肛门生殖器溃疡疾病为特征。症状的严重程度 慢性HSV-2感染者的变异性很大，这是一个尚无法解释的疾病特征。 虽然先前的研究主要集中在宿主在介导慢性HSV-2严重性中的作用， 感染，动物模型和人类研究的证据表明，病毒也可能发挥作用， 重要的作用这一建议的目的是提高我们对慢性胰腺炎发病机制的认识， 通过研究病毒因素对感染者所经历的症状严重程度的影响， 人士该提案包括三个目标。在目标1中，Casto博士将进行基因型-表型 关联研究，以扫描HSV-2基因组中与疾病严重程度相关的遗传变异。 这一目标将使用100个来自严重HSV-2疾病个体的HSV-2样本的基因组序列数据 （病例）和来自患有轻度疾病的个体的100个样品（对照）。一些遗传介导的特征是 由许多变量决定，每个变量的影响都很小。这种变异在基因型上很难识别- 表型关联研究，因此Casto博士还将评估HSV-2之间的其他内在差异 对应于疾病严重程度的样本。在目标2中，她将评估病毒基因表达的差异， 与疾病严重程度相关的基因， 来自病例和对照的病毒在体外生长。她还将比较病毒转录丰度， 来自病例和对照的HSV-2病变的活组织检查。在目标3中，她将评估病例中的病毒是否 在动物模型中比对照组的病毒引起更严重的疾病。这项工作的结果将提供 第一次深入了解病毒因素在决定慢性HSV-2疾病严重程度中的作用， 将有助于决定这一领域未来的研究方向。 博士卡斯托是过敏和传染病部门的代理讲师/高级研究员培训生， 华盛顿大学。她和她的导师们制定了一个全面的职业发展计划， 包括：1）与导师定期会面，讨论研究进展和职业发展; 2） 获得进行HSV体外和体内实验所需的技能; 3）重点课程 这增强了Casto博士在生物统计学，生物信息学和数据分析方面的技能; 4）参加研讨会 和讲习班，以发展卡斯托博士在科学交流和实验室管理方面的能力; 5） 参加地方，国家和国际会议，这将使博士。 在这个奖项结束时，卡斯托博士将过渡到独立作为一个调查员，运行她自己的实验室 致力于了解HSV和其他病毒感染的基因型-表型联系。

PROJECT SUMMARY Human herpes simplex virus 2 (HSV-2) is a sexually transmitted pathogen affecting 500 million people worldwide. Most of the global burden of HSV-2 disease results from the virus’s ability to establish chronic infections, characterized by recurrent anogenital ulcerative disease. The severity of symptoms experienced by those with chronic HSV-2 infection is highly variable, a feature of the disease which remains unexplained. While prior research has focused primarily on the role of the host in mediating the severity of chronic HSV-2 infection, evidence from studies both in animal models and humans suggests that the virus may also play an important role. The objective of this proposal is to improve our understanding of the pathogenesis of chronic HSV-2 infection by investigating the impact of viral factors on the severity of symptoms experienced by infected persons. The proposal consists of three aims. In Aim 1, Dr. Casto will perform a genotype-phenotype association study to scan the HSV-2 genome for genetic variants that are associated with disease severity. This aim will use genome sequence data for 100 HSV-2 samples from individuals with severe HSV-2 disease (cases) and for 100 samples from individuals with mild disease (controls). Some genetically-mediated traits are determined by many variants each with small effect. Such variants can be difficult to identify in genotype- phenotype association studies, so Dr. Casto will also assess for other intrinsic differences among HSV-2 samples that correspond to disease severity. In Aim 2, she will assess for differences in viral gene expression that are associated with disease severity by comparing the abundance of individual viral transcripts between viruses from cases and from controls grown in vitro. She will also compare viral transcript abundance in biopsies of HSV-2 lesions from cases and controls. In Aim 3, she will assess whether viruses from cases cause more severe disease in an animal model than viruses from controls. The results of this work will provide the first insights into the role of viral factors in determining the severity of chronic HSV-2 disease, insights that will help dictate the future direction of research in this field. Dr. Casto is an Acting Instructor/Senior Fellow Trainee in the Division of Allergy and Infectious Diseases at the University of Washington. She and her mentors have devised a comprehensive career development plan that includes: 1) Regular meetings with mentors to discuss research progress and career development; 2) Acquisition of the skills needed to perform in vitro and in vivo experiments with HSV; 3) Focused coursework that augments Dr. Casto’s skills in biostatistics, bioinformatics, and data analysis; 4) Attendance of seminars and workshops to develop Dr. Casto’s abilities in scientific communication and laboratory management; 5) Participation in local, national, and international conferences which will allow Dr. Casto to present her research. By the end of this award, Dr. Casto will transition to independence as an investigator, running her own lab dedicated to understanding genotype-phenotype connections for infections due to HSV and other viruses.