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.

项目概要 非编码 RNA (ncRNA) 构成了人类细胞内存在的大部分 RNA，并且是有效的 细胞过程的调节因子，包括翻译、剪接和转录后信使 RNA (mRNA) 控制。与人类一样，病毒也会产生 ncRNA，但其功能仍然很大程度上未知。鉴于病毒 为了最大限度地利用其小基因组中包含的信息，所有病毒 ncRNA 都被假定为 功能性的。我们的实验室研究小病毒 ncRNA 调节宿主和病毒的机制 过程，其知识将有助于开发治疗人类的新方法 疾病。在接下来的五年中，我们将阐明两种不同的病毒 ncRNA 类别的作用：小核 由致癌 g-疱疹病毒（项目 1）表达的 RNA (snRNA)，以及由 SARS-CoV-2，一种引起急性呼吸道疾病的病毒（项目 2）。 g-疱疹病毒是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多种蛋白质和多种 ncRNA。在潜伏期，疱疹病毒赛米里 (saimiri) 经典 g 疱疹病毒，表达七种 snRNA，称为 HSUR。与人类 snRNA 不同，HSUR 不 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 表明 HSUR 主要定位于细胞核，其作用仍未知。此外，我们 观察到 HSUR 选择性地将宿主细胞质 RNA 结合蛋白易位到细胞核中。在 项目1，我们将研究病毒snRNA的核作用，探索宿主未知的功能 RNA 结合蛋白并深入了解 g 疱疹病毒转化。 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 miRNA，命名为 CoV-miR-O7a，下调尤其涉及干扰素信号传导的宿主基因。我们的初步数据 研究表明，SARS-CoV-2 病毒颗粒内大量存在 CoV-miR-O7a。我们假设 CoV-miR-O7a （也许还有其他 ncRNA）被选择性地整合到病毒体中，以便对宿主基因进行早期操作 表达。在项目2中，我们将研究病毒miRNA掺入的机制和意义 进入新生病毒体，以了解 SARS-CoV-2 发病机制的未知方面，并 描述了病毒抑制宿主抗病毒反应的先前未探索的方式。 我们的多学科方法与 MIRA 资金的灵活性相结合，将导致 建立一个独特的研究项目，以了解小RNA生物学为中心 病毒感染。在阐明小病毒 ncRNA 的功能方面，这项研究将推动 RNA 生物学领域的发展 和病毒学。这些知识可以确定治疗病毒性疾病的新靶点，包括 病毒诱发的癌症。