The impact of viral genomic variation on neonatal disease outcomes

病毒基因组变异对新生儿疾病结果的影响

基本信息

批准号：
10453933
负责人：
MORIAH SZPARA
金额：
$ 61.98万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-04 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10453933
关键词：
Address Adult Animal Model Antibodies Antiviral Agents Body Surface Brain Categories Cell model Cells Central Nervous System Infections Cessation of life Clinical Clinical Course of Disease Clinical Data Clinical Management Congenital herpes simplex Consensus Data Data Set Diagnosis Dimensions Disease Disease Outcome Dissection Epithelial Eye Eye Infections Foundations Frequencies Future Genetic Genetic Variation Genome Genomics Genotype Goals Herpesvirus 1 High-Throughput Nucleotide Sequencing Human Human Herpesvirus 2 Immune Evasion Immune system Immunologics Impairment In Vitro Individual Infant Infection Infectious Skin Diseases Intervention Lesion Life Link Liver Location Lung Measures Minor Morbidity - disease rate Morphology Mothers Neonatal Neuraxis Neurologic Neurons Newborn Infant Oral cavity Organ Outcome Passive Immunization Pathogenesis Pattern Phenotype Population Proteins Risk Sampling Severities Severity of illness Simplexvirus Skin Therapeutic Intervention Time Translating United States Variant Viral Viral Proteins Virulence Virus Virus Diseases Virus Replication base cell type comparative genomics experience genetic variant genome wide association study genome-wide genomic locus genomic variation high risk improved in vivo in vivo Model in vivo evaluation infant infection mortality mouse model neonatal infection neonate neurovirulence novel phenotypic data predictive modeling protein expression protein function response skin disorder targeted treatment viral genomics virus culture virus genetics

项目摘要

The global burden of herpes simplex virus 1 (HSV1) is ~3.7 billion, while HSV2 afflicts ~400 million. In adults, these lifelong infections typically cause epithelial lesions, which recur whenever the virus reactivates from its lifelong latent reservoir in neurons. In newborns the outcomes are more dire, with approximately half of all HSV infections leading to invasive viral spread into the central nervous system (CNS), or viral dissemination into organs such as the lungs or liver. Rates of mortality and lifelong morbidity are significantly higher for the invasive CNS and disseminated forms of neonatal infection, than for infections that remain limited to the body surface. The contribution of HSV genetic variation to these different clinical outcomes is as yet unknown. In a recent pilot analysis of neonatal HSV samples, we found patterns of viral genetic variation that correlated with invasive spread phenotypes. We now propose to extend our genomic and phenotypic analyses of viral variation to a larger neonatal dataset and to incorporate in vivo models of virulence. The combination of viral comparative genomics, cell-based phenotyping, in vivo models of pathogenesis, and de-identified clinical data will lay the foundation for a future genome-wide association study (GWAS) for neonatal HSV. Using these data, we will probe connections between viral genetic variation and clinical outcomes such as invasive CNS vs. skin disease, severity of neurologic impairment, and response to antivirals. In Aim 1, we will use high-throughput sequencing (HTSeq) and comparative genomics to dissect viral genetic variation between and within individuals with HSV1 or HSV2 neonatal HSV disease. We will quantify differences between-hosts at the level of the overall consensus genomes, and within-host by examining minor variants in samples from distinct niches in the body. In Aim 2 we will determine the in vitro phenotypic profile of each cultured HSV isolate, by examining rates of viral replication, cell-to-cell spread, plaque morphology, and viral protein expression and localization in a panel of cell types, including neurons. In Aim 3 we will determine the rate of spread and neuroinvasion in vivo for neonatal HSV1 and HSV2 isolates, using murine models of either disseminated or CNS infection. These data will allow us to link differences in viral genetics (from Aim 1) and cell-based phenotypes (from Aim 2) with levels of neuroinvasion and virulence observed in vivo (Aim 3) or via de-identified clinical data for these neonatal isolates. Our ultimate goal is to find measures than can predict the risk of highly-invasive disease for newly infected newborns, so that individuals at highest risk can be identified and targeted for intervention(s) to limit viral invasion and improve clinical outcomes.

单纯疱疹病毒1（HSV1）的全球负担约为37亿，而HSV2折磨了约4亿。在成年人中，这些终身感染通常会引起上皮病变，每当病毒从其终生的潜在储层中反应到神经元中时，它们会复发。在新生儿中，结果更可怕，大约一半的HSV感染导致侵入性病毒传播到中枢神经系统（CNS）或病毒传播到肺或肝脏等器官中。对于侵入性中枢神经系统和传播的新生儿感染形式的死亡率和终生发病率明显高于仅限于身体表面的感染。 HSV遗传变异对这些不同的临床结果的贡献尚不清楚。在最近对新生儿HSV样品的试点分析中，我们发现了与侵入性扩散表型相关的病毒遗传变异模式。现在，我们建议将病毒变异的基因组和表型分析扩展到更大的新生儿数据集，并纳入毒力的体内模型。病毒比较基因组学，基于细胞的表型，发病机理模型和去识别的临床数据的组合将为新生儿HSV的未来全基因组关联研究（GWAS）奠定基础。使用这些数据，我们将探测病毒遗传变异与临床结果之间的联系，例如侵入性中枢神经系统与皮肤疾病，神经系统损害的严重程度以及对抗病毒药的反应。在AIM 1中，我们将使用高通量测序（HTSEQ）和比较基因组学来剖析HSV1或HSV2新生儿HSV疾病患者之间和内部的病毒遗传变异。我们将通过检查体内不同壁nir的样品中的样本中的次要变异来量化宿主之间的差异，并在宿主内进行差异。在AIM 2中，我们将通过检查病毒复制的速率，细胞到细胞扩散，斑块形态，病毒蛋白表达以及在包括神经元在内的细胞类型（包括神经元）中的局部定位来确定每个培养的HSV分离物的体外表型谱。在AIM 3中，我们将使用传播或中枢神经系统感染的鼠模型来确定新生儿HSV1和HSV2分离株在体内的扩散和神经入侵率。这些数据将使我们能够将病毒遗传学的差异（来自AIM 1）和基于细胞的表型（来自AIM 2）与体内观察到的神经侵袭和毒力水平联系起来（AIM 3），或通过这些新生儿分离株的去识别的临床数据。我们的最终目标是找到措施，而不是预测新感染新生儿的高度侵入性疾病的风险，以便可以确定和针对干预的人，以限制病毒入侵并改善临床结果。