Small RNA-mediated warfare between viruses and their hosts

小RNA介导的病毒与其宿主之间的战争

• 批准号: 10711930
• 负责人: Paulina Pawlica
• 金额: $ 19.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711930
• 关键词: 2019-nCoV; Acute; Antiviral Response; Biology; COVID-19; Cell Nucleus; Cell physiology; Cells; Coronavirus; Cytoplasm; DNA Viruses; Data; Development; Funding; Gene Expression; Genes; Genome; Herpesviridae; Human; Interferons; Knowledge; Mediating; Messenger RNA; MicroRNAs; Molecular; Names; Nuclear; Oncogenic; Pathway interactions; Process; Proteins; RNA; RNA Splicing; RNA Viruses; RNA, Messenger, Splicing; RNA-Binding Proteins; Research; Respiratory Disease; Role; SARS-CoV-2 pathogenesis; Saimiriine Herpesvirus 2; Signal Transduction; Small Nuclear RNA; Small RNA; Source; Transcript; Translations; Untranslated RNA; Viral; Viral Genes; Virion; Virus; Virus Diseases; Virus Latency; cell transformation; current pandemic; flexibility; human disease; insight; interdisciplinary approach; novel; novel strategies; posttranscriptional; programs; tumorigenesis; virology; virus related cancer

PROJECT SUMMARY Non-coding RNAs (ncRNAs) constitute the majority of RNAs present within the human cell, and are potent regulators of cellular processes, including translation, splicing, and post-transcriptional messenger RNA (mRNA) control. Like humans, viruses produce ncRNAs, whose functions are still largely unknown. Given that viruses evolved to maximize the information contained within their small genomes, all viral ncRNAs are postulated to be functional. Our lab studies the mechanisms by which small viral ncRNAs modulate host and viral processes, the knowledge of which will contribute to the development of new approaches to treat human disease. In the next five years, we will elucidate the roles of two distinct viral ncRNAs classes: small nuclear RNAs (snRNAs) expressed by an oncogenic g-herpesvirus (Project 1), and a microRNA (miRNA) produced by SARS-CoV-2, a virus that causes acute respiratory disease (Project 2). g-herpesviruses are DNA viruses, which during latency induce host cell transformation and oncogenesis. The latent viral genes produce several proteins and multiple ncRNAs. During its latency, herpesvirus saimiri, a classic g-herpesvirus, expresses seven snRNAs, known as HSURs. Unlike human snRNAs, HSURs were not linked to mRNA splicing, but instead to regulating host RNA levels in the cytoplasm. Interestingly, our results indicate that HSURs predominantly localize to the nucleus, where their roles remain unknown. Additionally, we observe that HSURs selectively translocate host cytoplasmic RNA-binding proteins into the nucleus. In Project 1, we will investigate the nuclear roles of viral snRNAs to explore unknown functions for host RNA-binding proteins and to gain insights into g-herpesviral transformation. SARS-CoV-2, a large RNA virus, is the causative agent of the coronavirus disease 2019 and the source of the current pandemic. We and others have recently discovered a miRNA expressed by SARS-CoV-2, named CoV-miR-O7a, which downregulates host genes involved inter alia in interferon signaling. Our preliminary data show that CoV-miR-O7a is abundantly present inside SARS-CoV-2 virions. We hypothesize that CoV-miR-O7a (and perhaps other ncRNAs) are selectively incorporated into virions to allow for early manipulation of host gene expression. In Project 2, we will investigate the mechanism and significance of viral miRNA incorporation into nascent virions to understand as yet unknown aspects of SARS-CoV-2 pathogenesis and to describe the previously unexplored way in which viruses inhibit host antiviral responses. Our multidisciplinary approaches, combined with the flexibility of MIRA funding, will lead to the establishment of a unique research program centered around understanding of small RNA biology in the context of viral infection. In elucidating functions of small viral ncRNAs, this study will advance the fields of RNA biology and virology. Such knowledge can lead to identification of novel targets for treatment of viral disease, including virally-induced cancers.

项目总结 非编码RNA(NcRNAs)构成了人类细胞内存在的大多数RNA，并且是有效的 细胞过程的调节，包括翻译、剪接和转录后信使RNA(MRNA) 控制力。像人类一样，病毒产生ncRNA，其功能在很大程度上仍不清楚。鉴于病毒 进化以最大限度地利用其小基因组中包含的信息，所有病毒ncRNA都被假设为 功能齐全。我们的实验室研究了小病毒ncRNA调节宿主和病毒的机制。 过程，其中的知识将有助于开发新的方法来治疗人类 疾病。在接下来的五年里，我们将阐明两类不同的病毒ncRNAs的作用：小核 由致癌g-疱疹病毒(项目1)表达的RNAs(SnRNAs)，以及由 SARS-CoV-2，一种导致急性呼吸道疾病的病毒(项目2)。 G-疱疹病毒是一种DNA病毒，在潜伏期诱导宿主细胞转化和肿瘤发生。 潜伏的病毒基因产生几种蛋白质和多个ncRNA。在潜伏期间，疱疹病毒塞米里病毒，一种 经典的g-疱疹病毒表达七个小RNA，称为HSURs。与人类的单链RNA不同，HSURs不是 与mRNA剪接有关，但与调节细胞质中的宿主RNA水平有关。有趣的是，我们的结果 这表明HSURs主要定位于核团，其作用尚不清楚。此外，我们 观察到HSURs选择性地将宿主细胞质RNA结合蛋白移位到细胞核中。在……里面 项目1，我们将研究病毒SnRNAs的核作用，以探索宿主未知的功能 RNA结合蛋白，并深入了解g-疱疹病毒的转化。 SARS-CoV-2是一种大型RNA病毒，是2019年冠状病毒病的病原体和来源 当前的大流行。我们和其他人最近发现了SARS-CoV-2表达的一种miRNA，命名为 CoV-miR-O7a，它下调涉及干扰素信号等的宿主基因。我们的初步数据 表明CoV-miR-O7a在SARS-CoV-2病毒粒子中大量存在。我们假设CoV-miR-O7a (也许还有其他ncRNA)被选择性地掺入病毒粒子中，以允许对宿主基因的早期操纵 表情。在项目2中，我们将研究病毒miRNA掺入的机制和意义 进入新生的病毒粒子，以了解SARS-CoV-2致病机理的未知方面，并 描述以前未曾探索过的病毒抑制宿主抗病毒反应的方式。 我们的多学科方法，加上Mira资金的灵活性，将导致 建立一个独特的研究计划，以了解背景下的小RNA生物学为中心 病毒感染的可能性。在阐明小病毒ncRNAs的功能方面，本研究将推动rna生物学领域的发展。 和病毒学。这种知识可导致确定治疗病毒疾病的新靶点，包括 病毒引起的癌症。