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

病毒因素对慢性HSV-2感染严重程度影响的调查

基本信息

批准号：
10673861
负责人：
Amanda Casto
金额：
$ 18.77万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-21 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673861
关键词：
Affect Animal Model Animals Area Award Bioinformatics Biological Models Biometry Biopsy Cavia Chronic Clinical Code Communicable Diseases Communication Data Data Analyses Data Set Dedications Development Plans Disease Educational workshop Equilibrium Frequencies Future Gene Expression Genes Genetic Variation Genetic study Genital Genitalia Genome Genotype Goals Herpesvirus 1 Heterogeneity Human Human Herpesvirus 2 Hypersensitivity Immune Immune Evasion Immune response Immune system Immunologic Deficiency Syndromes Immunosuppression In Vitro Individual Infection Integration Host Factors International Investigation Laboratories Lesion Mediating Mediator Mentors Methods Mutation Nucleic Acid Regulatory Sequences Pathogenesis Persons Phenotype Physicians Play Poly A Polyadenylation RNA Viruses Recurrence Research Research Personnel Role Running Sampling Scanning Scientist Severities Severity of illness Sexual Transmission Sexually Transmitted Diseases Simplexvirus Skin Subcutaneous Tissue Swab Symptoms Transcript Twin Studies Ulcer Universities Variant Viral Viral Genes Virus Virus Diseases Virus Replication Washington Work career development chronic infection differential expression ds-DNA experience experimental study genetic variant genital herpes genome sequencing genome wide association study guinea pig model human DNA improved in vivo in vivo Model insight instructor keratinocyte meetings microbial genome pathogen reproductive tract skill acquisition skills stem symposium trait transcriptome sequencing viral genomics viral transmission whole genome

项目摘要

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.

项目摘要人疱疹单纯疱疹病毒2（HSV-2）是一种性传播病原体，影响了5亿人全世界。 HSV-2疾病全球负担的大部分负担是由于病毒建立慢性的能力而产生的感染，其特征是复发性肛门生殖性溃疡性疾病。症状的严重程度患有慢性HSV-2感染的人高度可变，该疾病的特征仍然出乎意料。虽然先前的研究主要集中于宿主在介导慢性HSV-2的严重性中的作用感染，动物模型和人类研究的证据表明，该病毒也可能发挥作用重要角色。该建议的目的是提高我们对慢性发病机理的理解通过研究病毒因素对感染症状严重程度的影响，HSV-2感染人。该提案包括三个目标。在AIM 1中，Casto博士将执行基因型 - 表型协会研究扫描HSV-2基因组对与疾病严重程度相关的遗传变异体。该目标将使用严重HSV-2疾病个体的100个HSV-2样品使用基因组序列数据（病例）和来自轻度疾病个体（对照）的100个样本。一些遗传介导的特征是由许多变体确定，每个变体都具有较小的效果。这种变体在基因型中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与疾病严重程度相对应的样本。在AIM 2中，她将评估病毒基因表达的差异通过比较单个病毒转录本的抽象，与疾病的严重程度相关病例的病毒和体外生长的对照。她还将比较病毒笔录的丰度来自病例和对照的HSV-2病变活检。在AIM 3中，她将评估病毒是否来自病例与对照组相比，在动物模型中引起更严重的疾病。这项工作的结果将提供对病毒因素在确定慢性HSV-2疾病严重程度中的作用的最初见解，这是洞察力的见解。将有助于决定该领域研究的未来方向。 Casto博士是在过敏和传染病部门的代理讲师/高级学员华盛顿大学。她和她的导师制定了一项全面的职业发展计划包括：1）与导师的定期会议讨论研究进度和职业发展； 2）通过HSV进行体外和体内实验所需的技能； 3）专注的课程这增强了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）出勤和讲习班，以发展Casto博士在科学沟通和实验室管理方面的能力； 5）参加本地，国家和国际会议，这将使Casto博士能够介绍她的研究。在该奖项结束时，Casto博士将过渡到独立，并经营自己的实验室致力于理解由于HSV和其他病毒引起的感染的基因型 - 表型连接。