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 流感病毒是一种严重的公共卫生威胁，导致高发病率和死亡率。一年一度的疾病 流感带来的负担给我们的医疗基础设施和经济带来了巨大压力。这是尽管 通过每年接种疫苗、抗病毒药物疗法以及其他医疗和公共服务来控制疾病 健康干预措施。为了解决持续的健康和经济成本，显然需要更好地 了解流感病毒复制的分子机制以及如何操纵这些机制 治疗益处。流感病毒利用并在某些情况下破坏细胞因子和途径 促进复制。我们确定了病毒和宿主伙伴之间影响先天性的 RNA：蛋白质相互作用 感染期间的免疫反应。我们证明 IFIT2 是一种关键的细胞蛋白，可将病毒 mRNA 结合到 增强复制。这是令人惊讶的，因为 IFIT2 是响应病毒而表达的第一个蛋白质之一。 感染并表现出广谱抗病毒活性。 IFIT2 抗病毒活性的机制， 以及它如何被流感病毒纳入前病毒效应子，目前尚不清楚。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 分配了一个新活动 我们的数据表明，这是以前未被重视的抑制先天免疫反应策略的一部分。整体 该应用的目标是确定这些 RNA：蛋白质复合物如何由病毒和宿主组成 成分操纵先天免疫反应以支持病毒复制。在目标 1 中，我们研究 IFIT2 如何 在广泛的抗病毒反应中充当前线防御者。我们假设 IFIT2 增强 抗病毒蛋白的翻译，流感病毒重新利用这一事件来促进病毒的产生 蛋白质。我们使用实验来测试这一点，研究 IFIT2 与靶标 RNA 结合的过程， 影响其结合 mRNA 的翻译，并改变感染。目标 2 探讨之间相互作用的影响 病毒 NP 和宿主 RNA。这一目标表明 NP:RNA 复合物可调节先天免疫反应。我们 通过研究 RNA 和感染诱导的激活先天免疫途径的事件来研究这一点，以及 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平衡 有利于复制。此外，虽然我们的研究重点是流感病毒，但我们发现的潜在机制 将对宿主抗病毒反应和意外策略的一般理解产生广泛影响 被病毒用来对抗它们。完成本提案将提供基础知识，可以 有助于新的治疗方法或可用于合理开发的细胞靶点 抗流感病毒疗法。