Forward genetic prediction and testing of virulence loci in herpes simplex virus 1

单纯疱疹病毒1毒力位点的正向遗传预测和检测

• 批准号: 10338072
• 负责人: MORIAH SZPARA
• 金额: $ 39.44万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-23 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10338072
• 关键词: Address; Age; Animal Model; Antiviral Agents; Biochemical; Biological Assay; Clinical; Collection; DNA Viruses; Data; Diagnostic; Disease; Disease Outcome; Encephalitis; Engineering; Foundations; Frequencies; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genital; Genitalia; Genome; Genotype; Glean; Growth; Herpes Labialis; Herpesviridae; Herpesvirus 1; Human; Human Genetics; Human Herpesvirus 2; In Vitro; Individual; Infection; Knowledge; Lesion; Link; Measurable; Measures; Modeling; Modification; Molecular; Mus; Neuraxis; Neurons; Outcome; Pathogenesis; Peripheral Nervous System; Phenotype; Population; Proteins; Public Health; Recombinants; Recurrence; Reproducibility; Ribonucleases; Role; Severity of illness; Simplexvirus; Structure of trigeminal ganglion; Surface; Surveys; Testing; Trans-Activators; VP 16; Vaccines; Variant; Viral; Viral Genome; Viral reservoir; Virulence; Virulent; Virus; Virus Latency; base; chronic infection; experimental study; genome sequencing; genome wide association study; genomic data; genomic locus; in vivo; mouse model; ocular surface; oral cavity epithelium; pathogen; phenotypic data; predict clinical outcome; protein function; protein protein interaction; seropositive; tool; viral fitness; viral genomics; virus genetics

Project Summary Herpes simplex virus 1 (HSV-1) and HSV-2 cause millions of chronic infections. These viruses cause epithelial oral “cold” sores and genital lesions, which recur lifelong due to reactivation from a latent viral reservoir in neurons. Clinical outcomes from HSV-1 infection are highly diverse, ranging from surface lesions with quite different rates of recurrence, to asymptomatic shedding, to severe and potentially lethal encephalitis. This variation is thought to be caused by a combination of factors, including viral genetic differences, human genetic predisposition, and environmental variables. Animal models serve as the cornerstone of our molecular understanding of HSV-1 disease in vivo, and provide an opportunity to dissect viral genetic contributions to pathogenesis, while controlling for host genetic factors and environmental variables. We have recently sequenced a collection of low-passage clinical isolates of HSV-1 and categorized each isolate according to its reproducible virulence phenotype in a mouse ocular model of infection. We measured virulence in this model by the virus' ability to infect, replicate, and induce lethal disease, which involved the virus initiating infection at the ocular surface, migrating to the peripheral nervous system (trigeminal ganglia), and even penetrating into the central nervous system (CNS). Using multiple statistical approaches, we found two loci in the viral tegument protein VP22 (UL49) that predictably distinguish high-virulence clinical isolates from low-virulence isolates. VP22 is a viral tegument protein that is conserved among alpha-herpesviruses, which functions as a hub of viral and cellular protein interactions. VP22 functions in close concert with the viral transactivator protein VP16 (UL48), and the viral RNAse VHS (UL41). The variant loci detected in association with murine virulence exist at a frequency of approximately 50% in the clinical HSV-1 isolates we have surveyed to date, suggesting that knowledge gleaned from these experiments will provide data on viral variants of relevance to ongoing trials for antivirals and vaccines. With increased power from additional genotype-phenotype data, we will use a genome-wide association study (GWAS) to measure the association of VP22 and other candidate loci with virulence in HSV-1. We will make recombinant HSV-1 strains to test the role(s) of VP22 and other candidate virulence loci both in vivo and in vitro. We will test the hypothesis that virulent and non-virulent phenotypes in vivo result from distinct biochemical differences in VP22 between these isolates. Data from these experiments will enable us to test the robustness of our forward genetic predictions of virulence loci in HSV-1. If these data can be linked to human impacts in the future, the ability to gauge likely virulence level based on viral genotype would provide a powerful tool for future diagnostics and prediction of clinical outcomes.

项目摘要 单纯疱疹病毒1型(HSV-1)和单纯疱疹病毒2型(HSV-2)导致数百万人慢性感染。这些病毒会导致 口腔上皮性“冷疮”和生殖器损伤，由于潜伏病毒的重新激活而终生复发 储藏在神经元中。HSV-1感染的临床结果差异很大，从表面到表面 复发率、无症状脱落、严重和潜在致命率有很大不同的病变 脑炎。这种变异被认为是由多种因素引起的，包括病毒遗传 差异、人类遗传易感性和环境变量。动物模型充当了 为我们在体内了解HSV-1疾病的分子基础，并提供了一个机会 剖析病毒遗传对致病的贡献，同时控制宿主遗传因素和 环境变量。 我们最近对一组低传代的HSV-1临床分离株进行了测序，并对每一株进行了分类 在小鼠眼部感染模型中根据其可复制的毒力表型进行分离。我们 在这个模型中，通过病毒感染、复制和诱导致命疾病的能力来衡量毒力，这 涉及病毒在眼表发起感染，迁移到周围神经系统 (三叉神经节)，甚至进入中枢神经系统(CNS)。使用多个 统计方法，我们在病毒被膜蛋白VP22(UL49)中发现了两个可预测的基因座 区分高毒力临床分离株与低毒力分离株。VP22是一种病毒被膜蛋白 这在阿尔法疱疹病毒中是保守的，它是病毒和细胞蛋白的枢纽。 互动。VP22与病毒反式激活蛋白VP16(UL48)的功能密切一致，并且 病毒核酸酶VHS(UL41)。检测到的与小鼠毒力相关的变异基因座存在于 到目前为止，我们调查的HSV-1临床分离株的频率约为50%，这表明 从这些实验中收集的知识将提供与正在进行的病毒变异相关的数据 抗病毒药物和疫苗的试验。 随着额外的基因-表型数据的增强，我们将使用全基因组关联 检测VP22和其他候选基因座与HSV-1毒力的相关性。我们 将使重组单纯疱疹病毒1型毒株检测VP22和其他候选毒力基因座对S的作用 体内和体外。我们将检验这样一种假设，即体内的毒力和非毒力表型是由 这些分离株在VP22上存在明显的生化差异。这些实验的数据将使 以测试我们对HSV-1毒力基因座正向遗传预测的稳健性。如果这些数据可以 与人类未来的影响相联系，基于病毒评估可能的毒力水平的能力 基因分型将为未来的诊断和临床结果的预测提供强有力的工具。

项目成果

ICTV Virus Taxonomy Profile: Herpesviridae 2021.

• DOI: 10.1099/jgv.0.001673
• 发表时间: 2021-10
• 期刊: The Journal of general virology
• 作者: Gatherer D;Depledge DP;Hartley CA;Szpara ML;Vaz PK;Benkő M;Brandt CR;Bryant NA;Dastjerdi A;Doszpoly A;Gompels UA;Inoue N;Jarosinski KW;Kaul R;Lacoste V;Norberg P;Origgi FC;Orton RJ;Pellett PE;Schmid DS;Spatz SJ;Stewart JP;Trimpert J;Waltzek TB;Davison AJ
• 通讯作者: Davison AJ

Multi-phenotype analysis for enhanced classification of 11 herpes simplex virus 1 strains.

• DOI: 10.1099/jgv.0.001780
• 发表时间: 2022-10
• 期刊: JOURNAL OF GENERAL VIROLOGY
• 影响因子: 3.8
• 作者: Dweikat, Sarah N;Renner, Daniel W;Bowen, Christopher D;Szpara, Moriah L
• 通讯作者: Szpara, Moriah L

A holistic perspective on herpes simplex virus (HSV) ecology and evolution.

• DOI: 10.1016/bs.aivir.2021.05.001
• 发表时间: 2021
• 期刊: Advances in virus research
• 作者: Rathbun MM;Szpara ML
• 通讯作者: Szpara ML

Dermatitis during Spaceflight Associated with HSV-1 Reactivation.

• DOI: 10.3390/v14040789
• 发表时间: 2022-04-11
• 期刊: Viruses

Genome Sequence of the Virulent Model Herpes Simplex Virus 1 Strain McKrae Demonstrates the Presence of at Least Two Widely Used Variant Strains.

• DOI: 10.1128/mra.01146-19
• 发表时间: 2021-03-25
• 期刊: Microbiology resource announcements
• 影响因子: 0.8
• 作者: Renner DW;Parsons L;Shreve JT;Engel EA;Kuny CV;Enquist L;Neumann D;Mangold C;Szpara ML
• 通讯作者: Szpara ML