Astrovirus CNS Infections

星状病毒中枢神经系统感染

基本信息

批准号：
10514627
负责人：
Stacey L Schultz-Cherry
金额：
$ 9.1万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
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：
2021-11-01 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10514627
关键词：
Adult Astrocytes Astrovirus Blood - brain barrier anatomy Brain Brain Stem Cell Culture Techniques Cell Death Cell Line Cell physiology Cells Cellular Tropism Central Nervous System Central Nervous System Diseases Central Nervous System Infections Cerebellum Cessation of life Child Clinical Coculture Techniques Collaborations Complex Diagnosis Diagnostic Disease Encephalitis Endothelial Cells Etiology Faculty Family Gastroenteritis Genotype Goals Hospitals Human Immunocompromised Host Infection Inflammatory Interferons Intervention Kinetics Knowledge Laboratories Life Literature Mammals Medical Meningitis Microglia Modeling Myelitis Neurobiology Neurologic Neurons Neurovirology Pathogenesis Patients Pediatric Oncology Persons Production Productivity Property Qualifying Supporting Cell of the Nervous System System Testing Therapeutic Universities Virus Virus Replication Wisconsin Work biomarker identification cytokine developmental neurobiology in vivo long-term sequelae nerve stem cell pediatric patients response transcriptomics

项目摘要

OVERALL ABSTRACT Infections of the central nervous system (CNS) are potentially life-threatening and can cause long-term neurological sequelae in patients that survive. Yet, CNS infections remain a diagnostic conundrum with over 50% of cases requiring management without the identification of an etiology. We and others have recently demonstrated that astroviruses, a leading cause of gastroenteritis, are also neuroinvasive. There is a significant gap in our understanding of astrovirus-associated CNS disease. The overall goal of these studies is to fill this gap in knowledge by defining the cellular tropism of astrovirus for CNS cells and the impact of infection on cellular function. The rigor of this proposal is supported by our preliminary studies demonstrating that two genetically distinct human astrovirus strains productively replicate in blood-brain barrier endothelial (BBE) cells and from literature showing astrovirus replication in astrocytes and SK-N-SH cell line. We hypothesize that numerous human astrovirus genotypes, both lab and clinical isolates, will productively replicate in CNS cells impacting cellular function. To test this hypothesis, we have developed the following specific aims: 1. Identify the CNS cells that support astrovirus replication. 2. Determine if replication in CNS cells is specific to VA1 or a property of all human astroviruses. 3. Define the impact of infection on cellular function. My laboratory is uniquely qualified to undertake this work given our long-standing expertise in astrovirus pathogenesis. The death of one of our pediatric patients due to astrovirus-associated CNS infection led us to expand into CNS infection. The studies will be performed in collaboration with St Jude colleagues with expertise in neurobiology including Dr. Elaine Tuomanen (ID), faculty within the Department of Developmental Neurobiology and Dr. Kristen Bernard at the University of Wisconsin, a neurovirology expert. The proposed work will be the basis for follow on studies to determine how astrovirus gets to the brain, examine long-term sequelae, therapeutic strategies, and potentially identify biomarkers of astrovirus-induced CNS.

总体摘要中枢神经系统 (CNS) 感染可能危及生命，并可能导致长期幸存患者的神经系统后遗症。然而，中枢神经系统感染仍然是一个诊断难题， 50% 的病例需要在未确定病因的情况下进行治疗。我们和其他人最近证明星状病毒是胃肠炎的主要原因，也是神经侵袭性的。有一个我们对星状病毒相关中枢神经系统疾病的理解存在重大差距。这些研究的总体目标是通过定义星状病毒对中枢神经系统细胞的细胞向性以及其影响来填补这一知识空白感染对细胞功能的影响。我们的初步研究证明了这一提议的严谨性，表明两种基因不同的人类星状病毒株可在血脑屏障内皮 (BBE) 细胞中高效复制，并且文献报道显示星形病毒在星形胶质细胞和 SK-N-SH 细胞系中的复制。我们假设许多人类实验室和临床分离的星状病毒基因型将在影响细胞的中枢神经系统细胞中高效复制功能。为了检验这一假设，我们制定了以下具体目标： 1. 识别支持星状病毒复制的 CNS 细胞。 2. 确定 CNS 细胞中的复制是否是 VA1 特有的还是所有人类星状病毒的特性。 3. 定义感染对细胞功能的影响。鉴于我们在星状病毒方面的长期专业知识，我的实验室具有承担这项工作的独特资格发病。我们的一名儿科患者因星状病毒相关的中枢神经系统感染而死亡，这导致我们扩展到中枢神经系统感染。这些研究将与 St Jude 的同事合作进行神经生物学方面的专业知识，包括发育系教员 Elaine Tuomanen 博士（ID）神经生物学和威斯康星大学神经病毒学专家克里斯汀·伯纳德博士。拟议的这项工作将成为后续研究的基础，以确定星状病毒如何进入大脑，并进行长期研究后遗症、治疗策略，并可能识别星状病毒诱导的中枢神经系统的生物标志物。