RNA:protein interactions that dictate the success of influenza virus infection

RNA：决定流感病毒感染成功与否的蛋白质相互作用

• 批准号: 10560604
• 负责人: Andrew Mehle
• 金额: $ 68.54万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-02 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560604
• 关键词: Address; Affect; Antiviral Agents; Antiviral Response; Binding; Binding Proteins; Cells; Complex; Data; Detection; Development; Environment; Equilibrium; Event; Goals; Health Care Costs; Healthcare; Immune; Impairment; Infection; Influenza; Infrastructure; Innate Immune Response; Integration Host Factors; Interferons; Invaded; Knowledge; Medical; Messenger RNA; Molecular; Morbidity - disease rate; Nucleic Acids; Nucleoproteins; Outcome; Pathway interactions; Pattern recognition receptor; Pharmacotherapy; Process; Production; Productivity; Proteins; Public Health; RNA; RNA amplification; RNA-Protein Interaction; Recurrence; Research; Ribosomes; Role; Severities; Shapes; Strategic Planning; Testing; Therapeutic; Therapeutic Intervention; Translations; United States National Institutes of Health; Vaccination; Viral; Viral Physiology; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; anti-influenza; burden of illness; cellular targeting; direct application; disorder control; economic cost; experimental study; gene product; genetic association; immune activation; immunogenic; influenza infection; influenza outbreak; influenzavirus; innate immune pathways; insight; mortality; new therapeutic target; novel; novel therapeutic intervention; pandemic disease; pathogen; prevent; protein complex; public health intervention; response; seasonal influenza; sensor; success; universal influenza vaccine; viral RNA

ABSTRACT Influenza virus is a serious public health threat causing high levels of morbidity and mortality. The annual disease burden from influenza places a significant strain on our healthcare infrastructure and economy. This is despite many efforts to control disease with yearly vaccination, antiviral drug therapies, and other medical and public health interventions. To address the continuing health and economic costs, there is a clear need to better understand the molecular mechanisms of influenza virus replication and how these can be manipulated for therapeutic benefit. Influenza virus exploits, and in some cases subverts, cellular factors and pathways to promote replication. We identified RNA:protein interactions between viral and host partners that impact innate immune responses during infection. We showed IFIT2 is a critical cellular protein that binds viral mRNAs to enhance replication. This was surprising, as IFIT2 is one of the first proteins expressed in response to viral infection and displays broad-spectrum antiviral activity. The mechanisms underlying the antiviral activity of IFIT2, and how this is co-opted into a proviral effector by influenza virus, are not yet known. We also showed that influenza nucleoprotein (NP) is a key viral protein that binds host RNAs. This assigns a new activity to NP that our data suggest is part of a previously unappreciated strategy to dampen innate immune responses. The overall goal of this application is to determine how these RNA:protein complexes composed of both viral and host components manipulate innate immune responses to support viral replication. In Aim 1, we investigate how IFIT2 functions as a front-line defender in a broadly acting antiviral response. We hypothesize that IFIT2 enhances translation of antiviral proteins, an event that is repurposed by influenza virus to promote production of viral proteins. We test this using experiments that investigate the processes by which IFIT2 engages target RNAs, affects translation of its bound mRNAs, and alters infection. Aim 2 interrogates the impact of interactions between viral NP and host RNAs. This aim proposes that NP:RNA complexes moderate innate immune responses. We investigate this by studying RNAs and infection-induced events that activate innate immune pathways, and discern the impact on viral replication. The results from this proposal will establish a mechanistic understanding of the viral and host factors regulating innate immune responses and how influenza virus tips the balance to favor replication. Moreover, while our studies focus on influenza virus, the underlying mechanisms we discover will have broad impacts on the general understanding of host antiviral responses and unexpected strategies used by viruses to counteract them. Completion of this proposal will provide fundamental knowledge that can contribute to new therapeutic approaches or cellular targets that can be exploited for the rational development of anti-influenza virus therapies.

抽象的 流感病毒是严重的公共卫生威胁，导致高水平的发病率和死亡率。年度疾病 流感的负担对我们的医疗基础设施和经济产生了重大压力。尽管如此 通过年度疫苗接种，抗病毒药疗法以​​及其他医学和公众来控制疾病的许多努力 健康干预措施。为了解决持续的健康和经济成本，显然需要更好 了解流感病毒复制的分子机制，以及如何对其进行操纵 治疗益处。流感病毒的利用，在某些情况下颠覆，细胞因素和途径 促进复制。我们确定了RNA：病毒与宿主伴侣之间的蛋白质相互作用，影响先天 感染过程中的免疫反应。我们显示IFIT2是一种关键的细胞蛋白，它结合病毒mRNA与 增强复制。这是令人惊讶的，因为IFIT2是对病毒的第一个蛋白质之一 感染和显示广谱抗病毒活性。 IFIT2抗病毒活性的基础机制， 尚不清楚如何将其选择为流感病毒的病毒效应子。我们还表明 流感核蛋白（NP）是结合宿主RNA的关键病毒蛋白。这为NP分配了一项新活动 我们的数据表明，这是以前未经批准的抑制先天免疫反应的策略的一部分。总体 该应用的目的是确定这些RNA：由病毒和宿主组成的蛋白质复合物如何 组件操纵先天免疫反应以支持病毒复制。在AIM 1中，我们研究了IFIT2如何 在广泛作用的抗病毒反应中充当前线防守者。我们假设IFIT2增强了 抗病毒蛋白的翻译，这一事件由流感病毒重新利用以促进病毒的产生 蛋白质。我们使用研究IFIT2参与目标RNA的过程的实验进行测试 影响其绑定的mRNA的翻译，并改变感染。目标2询问互动的影响 病毒NP和宿主RNA。该目标提出NP：RNA复合物可中等先天免疫反应。我们 通过研究RNA和感染诱导的事件来调查这一点，以激活先天免疫途径，并 辨别对病毒复制的影响。该提案的结果将建立机械理解 调节先天免疫反应的病毒和宿主因素，以及流感病毒如何使平衡趋向于 喜欢复制。此外，尽管我们的研究专注于流感病毒，但我们发现的基本机制 将对宿主抗病毒反应和意外策略的一般理解产生广泛的影响 病毒用来抵消它们。该提案的完成将提供基本知识 有助于新的治疗方法或细胞靶标，可以利用合理发展 抗炎性病毒疗法。