Astrovirus CNS Infections

总体摘要 中枢神经系统(CNS)的感染可能危及生命，并可能导致长期的 存活患者的神经后遗症。然而，中枢神经系统感染仍然是一个诊断难题， 50%的病例在没有确定病因的情况下需要处理。我们和其他人最近 证明了星状病毒是胃肠炎的主要原因，也是神经侵入性的。有一个 在我们对星状病毒相关的中枢神经系统疾病的理解上存在显著差距。这些研究的总体目标是 通过确定星形病毒对中枢神经系统细胞的趋向性以及星形病毒对 对细胞功能的感染。 这一提议的严谨性得到了我们的初步研究的支持，该研究表明，两种不同的基因 人类星形病毒株在血脑屏障内皮细胞中高效复制 在星形胶质细胞和SK-N-SH细胞系中显示星形病毒复制。我们假设许多人类 星状病毒的实验室和临床分离株将在影响细胞的中枢神经系统细胞中高效复制 功能。为了验证这一假设，我们制定了以下具体目标： 1.确定支持星形病毒复制的中枢神经系统细胞。 2.确定中枢神经系统细胞中的复制是否是VA1特有的，还是所有人类星形病毒的特性。 3.确定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，我的实验室是唯一有资格承担这项工作的人。 发病机制。我们的一名儿科患者死于星状病毒相关的中枢神经系统感染，导致我们 扩展到中枢神经系统感染。这些研究将与圣犹大的同事合作进行， 神经生物学方面的专门知识，包括Elaine Tuomanen博士(ID)，发育系教员 神经生物学和威斯康星大学的神经病毒学专家克里斯汀·伯纳德博士。建议数 这项工作将是后续研究的基础，以确定星状病毒是如何到达大脑的，检查长期 后遗症，治疗策略，并可能确定星形病毒诱导的中枢神经系统的生物标记物。

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.