Astrovirus CNS Infections

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 神经系统后遗症的患者。然而，中枢神经系统感染仍然是一个诊断难题， 50%的病例需要管理，但未确定病因。我们和其他人最近 研究表明，导致胃肠炎的主要原因星状病毒也具有神经侵袭性。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CNS细胞的细胞嗜性以及 感染对细胞功能的影响。 我们的初步研究表明，两种遗传上不同的 人星状病毒株在血脑屏障内皮（BBE）细胞中高效复制和来自文献 显示星形胶质细胞和SK-N-SH细胞系中的星形病毒复制。我们假设许多人类 星状病毒基因型，实验室和临床分离株，将在中枢神经系统细胞中有效复制，影响细胞 功能为了验证这一假设，我们制定了以下具体目标： 1.鉴定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VA 1特异性的或所有人类星状病毒的特性。 3.定义感染对细胞功能的影响。 我的实验室是唯一有资格承担这项工作鉴于我们长期的专业知识在星状病毒 发病机制我们的一名儿科患者因星状病毒相关CNS感染死亡， 发展成中枢神经系统感染这些研究将与圣犹达的同事合作进行， 在神经生物学的专业知识，包括博士伊莱恩Tuomanen（ID），在发展系教师 神经生物学和威斯康星州大学的神经病毒学专家克里斯汀·伯纳德博士说。拟议 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， 后遗症、治疗策略和可能鉴定星状病毒诱导CNS的生物标志物。

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.