The Role of Host-Encoded microRNAs in Maintaining Measles Virus Persistence

描述（由申请人提供）：尽管疫苗接种工作普遍成功，但麻疹病毒（MV）仍然是可预防疾病和死亡的主要原因，每年造成约3000万急性感染，导致约1.5 -20万人死亡。该病毒具有侵入中枢神经系统（CNS）并在神经元内形成明显的非细胞病变、持续性感染的良好倾向，最近的一些证据表明，这种持续性也可能发生在其他器官。然而，允许这种高度细胞病变病毒持续存在的因素仍然未知。MicroRNAs （miRs）是一类长约22nt的非编码rna，从所有多细胞生物和某些病毒的基因组中转录而来。特异性miRs与发育、分化、增殖、凋亡和肿瘤发生有关，单个miRs可能调节数百个基因。在本研究中，作者以病毒为模型系统，探讨了宿主编码的miRs对持续感染的建立和维持的潜在贡献。核心假设是，MV（不编码miRs）可以调节宿主细胞编码的miRs的表达谱和水平，从而调节具有已知免疫调节特性的靶基因的表达。标准的生物学和生物信息学工具将用于确定宿主编码的miRs的表达谱和水平，候选miRs的靶标将被识别和实验操作，以确定细胞蛋白表达改变与病毒生命周期状态之间的机制联系。重点将放在干扰素信号通路内的基因（Aim 1），以及那些可能直接结合病毒基因组的miRs （Aim 2）。在非细胞病变感染期间，对MV与其宿主细胞之间相互作用的更明确的理解可能会确定解决导致人类疾病的慢性病毒感染的新策略。

DESCRIPTION (provided by applicant): Despite generally successful vaccination efforts, measles virus (MV) remains a leading cause of preventable illness and death, causing an estimated 30 million acute infections that result in ~150-200,000 deaths annually. The virus has a well-established propensity to invade the central nervous system (CNS) and develop an apparently noncytopathic, persistent infection within neurons, and some recent evidence suggests that persistence may occur in other organs as well. However, the factors that allow this otherwise highly cytopathic virus to persist remain unknown. MicroRNAs (miRs) are a class of ~22 nt long noncoding RNAs transcribed from the genomes of all multicellular organisms and some viruses. Specific miRs have been implicated in development, differentiation, proliferation, apoptosis, and oncogenesis, and individual miRs may regulate several hundred genes. In this proposal, the potential contribution of host-encoded miRs to the establishment and maintenance of persistent infections is explored using MV as a model system. The core hypothesis is that MV (which does not encode miRs) can nevertheless modulate the expression profile and levels of host cell- encoded miRs, thus regulating the expression of target genes with known immunomodulatory characteristics. Standard biological and bioinformatic tools will be used to determine the expression profile and levels of host- encoded miRs, and targets for candidate miRs will be identified and experimentally manipulated to identify mechanistic links between altered expression of cellular proteins and the status of the viral life cycle. Emphasis will be placed on genes within interferon signaling pathways (Aim 1), and those miRs that may directly bind to the viral genome (Aim 2). A more defined understanding of the interplay between MV and its host cell during noncytopathic infection may identify novel strategies to resolve chronic viral infections that contribute to human disease. PUBLIC HEALTH RELEVANCE: Despite increased attention to the potential role of chronic viral infections in human disease, little is known about the factors that favor establishment of noncytolytic infections. In this proposal, two collaborating investigators with complementary expertise will pursue preliminary efforts that found unique microRNA expression profiles associated with chronic measles virus infection in cell lines. The potential of these microRNAs to influence cellular gene expression, which in turn may foster a cellular environment conducive to viral persistence, will be explored.