tRNA-derived RNA Fragments and their Role in Nasal SARS-CoV-2 Infection

tRNA 衍生的 RNA 片段及其在鼻 SARS-CoV-2 感染中的作用

基本信息

批准号：
10655651
负责人：
Xiaoyong Bao
金额：
$ 20万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655651
关键词：
2019-nCoV 5 year old Acute Respiratory Distress Syndrome Affect Animals Anticodon Antiviral Agents Biogenesis Biological Biological Assay Biological Markers COVID-19 COVID-19 pandemic COVID-19 treatment Cause of Death Cell model Cessation of life Clinical Trials Collaborations Communicable Diseases Coughing Data Development Disease Dose Economic Recession Emerging Communicable Diseases Enzymes Epidemiology Epithelial Cells Failure Family Fever Functional disorder Future Genetic Transcription Goals Headache Hepatitis C virus Hepatitis Viruses Home Human Immune response Immunity Individual Infection International Laboratories Location Longevity Methods Molecular Myalgia Nasal Epithelium Nose Organ Outcome Parents Patients Pharmaceutical Preparations Pharyngeal structure Population Protocols documentation Quantitative Reverse Transcriptase PCR RNA RNA Viruses RNA chemical synthesis Research Research Personnel Resources Respiratory Syncytial Virus Infections Respiratory syncytial virus Role SARS coronavirus SARS-CoV-2 infection SARS-CoV-2 pathogenesis Sampling Shortness of Breath Solid Sore Throat Symptoms System Techniques Testing Therapeutic Therapeutic Intervention Transfer RNA Untranslated RNA Upper respiratory tract Vaccination Vaccinee Vaccines Viral Viral Genes Viral Load result Virus Virus Diseases Virus Replication airway epithelium antiviral drug development cell injury clinical application design effective therapy experience gain of function inhibitor innovation insight loss of function nasal swab novel novel therapeutic intervention pathogenic virus response therapeutic development therapeutic target therapeutically effective transcriptome sequencing vaccine access vaccine effectiveness viral RNA

项目摘要

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an emerging pathogenic virus, has resulted in not only the coronavirus disease 2019 (COVID-19) pandemic, but also economic recession. To strategically develop antiviral therapies against SARS-CoV-2, a focused effort in identifying mechanisms on how the host responds to SARS-CoV-2 is urgently needed. Non-coding RNAs (ncRNAs) contribute to 98% of human transcriptional products and are promising therapeutic targets against viral infections. One effective example for utilizing ncRNAs as promising therapeutic targets is that miR122 inhibitor RG-101 suppresses the hepatitis C virus (HCV) with a single dose. Therefore, studying the ncRNA responses for emerging viruses may provide a shortcut to developing effective therapeutic interventions. We recently discovered that the most impacted small ncRNAs (sncRNAs) by SARS-CoV-2 in nasal swab samples belong to tRNA-derived RNA Fragments (tRFs), a recently discovered ncRNA family. We also found that SARS-CoV-2-induced tRFs are unlikely to be degradation byproducts, but tightly regulated molecules, and nasal airway epithelial cells (AECs) can recapitulate tRF induction by SARS-CoV-2. Compared with tRFs induced by hepatitis viruses and respiratory syncytial virus (RSV), SARS-CoV-2-induced tRFs share several features with them. Given the emerging roles of tRFs in other viral infections, including our early observation on their proviral role in RSV infection and our preliminary data validating a SARS-CoV-2-induced tRF being important in regulating viral RNA synthesis, we hypothesize that SARS-CoV-2-induced tRFs are also functionally important to SARS-CoV-2 infection. We will address the hypothesis by 1) characterizing tRF signatures, and 2) investigating whether tRFs affect SARS-CoV-2 replication and associated host responses. UTMB is the home of the BSL4 Galveston National Laboratory (GNL), a leading resource for our national response to emerging infectious diseases. The GNL obtained the first sample of SARS- CoV-19 at the end of January of 2020, and is currently conducting research on all fronts; basic, animal, clinical trials, and epidemiological. We have an ongoing collaboration with co-investigator Dr. Tian Wang, who is an expert in studying host responses to BSL3 RNA viruses. Her laboratory has established a protocol to purify SARS-CoV-2 for the infection. We recently have been working together on AEC models to study the interaction between host and SARS-CoV-2. The results of this project will not only provide the potential to determine the molecular mechanisms associated with the replication and pathogenesis of SARS-CoV-2, but also are highly instructive for the development of potential disease biomarkers and therapeutic strategies for SARS-CoV-2. In conclusion, the overall goal of our team is to provide ncRNAs-related information for designing novel antiviral drugs.

严重急性呼吸综合征冠状病毒2（SARS-CoV-2）这种新出现的致病病毒的传播不仅导致了2019年冠状病毒病（COVID-19）大流行，还导致了经济衰退。为了战略性地开发针对 SARS-CoV-2 的抗病毒疗法，迫切需要集中精力确定宿主如何应对 SARS-CoV-2 的机制。非编码 RNA (ncRNA) 贡献了 98% 的人类转录产物，是对抗病毒感染的有希望的治疗靶点。利用 ncRNA 作为有希望的治疗靶点的一个有效例子是 miR122 抑制剂 RG-101 单剂量即可抑制丙型肝炎病毒 (HCV)。因此，研究新兴病毒的 ncRNA 反应可能为开发有效的治疗干预措施提供一条捷径。我们最近发现，鼻拭子样本中受 SARS-CoV-2 影响最大的小 ncRNA (sncRNA) 属于 tRNA 衍生的 RNA 片段 (tRF)，这是最近发现的 ncRNA 家族。我们还发现 SARS-CoV-2 诱导的 tRF 不太可能是降解副产物，而是严格调控的分子，鼻气道上皮细胞 (AEC) 可以重现 SARS-CoV-2 诱导的 tRF。与肝炎病毒和呼吸道合胞病毒（RSV）诱导的 tRF 相比，SARS-CoV-2 诱导的 tRF 有几个共同特征。鉴于 tRF 在其他病毒感染中的新作用，包括我们对其在 RSV 感染中的原病毒作用的早期观察，以及我们验证 SARS-CoV-2 诱导的 tRF 在调节病毒 RNA 合成中的重要作用的初步数据，我们假设 SARS-CoV -2 诱导的 tRF 对 SARS-CoV-2 感染也具有重要的功能。我们将通过 1) 表征 tRF 特征，以及 2) 调查 tRF 是否影响 SARS-CoV-2 复制和相关宿主反应来解决这一假设。 UTMB 是 BSL4 加尔维斯顿国家实验室 (GNL) 的所在地，该实验室是我们国家应对新发传染病的领先资源。 GNL于2020年1月底获得了第一个SARS-CoV-19样本，目前正在开展各方面的研究；基础、动物、临床试验和流行病学。我们与共同研究员 Tian Wang 博士正在进行合作，Tian Wang 博士是研究 BSL3 RNA 病毒宿主反应的专家。她的实验室已经制定了纯化 SARS-CoV-2 感染的方案。我们最近一直在合作开发 AEC 模型，以研究宿主和 SARS-CoV-2 之间的相互作用。该项目的结果不仅将为确定与 SARS-CoV-2 复制和发病机制相关的分子机制提供潜力，而且对于开发 SARS-CoV-2 潜在疾病生物标志物和治疗策略具有高度指导意义。总之，我们团队的总体目标是为设计新型抗病毒药物提供 ncRNA 相关信息。