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

• 批准号: 10867808
• 负责人: Xiaoyong Bao
• 金额: $ 24万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 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/10867808
• 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

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.

新兴的致病性病毒（SARS-COV-2）严重急性呼吸综合征的传播不仅导致2019年冠状病毒病（COVID-19）大流行，而且导致经济衰退。为了在战略上开发针对SARS-COV-2的抗病毒疗法，迫切需要迫切需要识别宿主对SARS-COV-2的响应机制的重点努力。非编码RNA（NCRNA）贡献了98％的人类转录产物，并且是针对病毒感染的有前途的治疗靶标。利用NCRNA作为有前途的治疗靶标的一个有效的例子是，miR122抑制剂RG-101用单剂量抑制丙型肝炎病毒（HCV）。因此，研究新兴病毒的NCRNA反应可能会为开发有效的治疗干预措施提供捷径。我们最近发现，鼻拭子样品中SARS-COV-2受影响最大的小NCRNA（SNCRNA）属于tRNA衍生的RNA片段（TRF），这是一个最近发现的NCRNA家族。我们还发现，SARS-COV-2诱导的TRF不太可能是降解副产品，但是严格调节的分子，鼻气道上皮细胞（AEC）可以通过SARS-COV-2概括TRF诱导。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与它们具有多个特征。鉴于TRF在其他病毒感染中的新作用，包括我们对它们在RSV感染中的前期作用的早期观察以及我们的初步数据验证了SARS-COV-2-2引起的TRF在调节病毒RNA合成中很重要，我们假设SARS-COV-2-COV-2诱导的TRF对SARS-COV诱导的TRF对SARS-COV-COV-2-2也很重要。我们将通过1）表征TRF签名来解决该假设，以及2）研究TRF是否影响SARS-COV-2复制和相关的宿主反应。 UTMB是BSL4 Galveston国家实验室（GNL）的所在地，这是我们国家对新兴传染病的反应的主要资源。 GNL于2020年1月底获得了SARS-COV-19的第一个样本，目前正在对所有方面进行研究。基础，动物，临床试验和流行病学。我们与共同投资者Tian Wang博士进行了持续的合作，他是研究宿主对BSL3 RNA病毒的反应的专家。她的实验室已经建立了一项协议，以净化SARS-COV-2的感染。最近，我们一直在研究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的复制和发病机理相关的分子机制提供潜力，而且对发展潜在疾病生物标志物的发展和SARS-COV-2的治疗策略具有很高的启发性。总之，我们团队的总体目标是提供与NCRNA相关的信息，以设计新型抗病毒药。

项目成果

Editorial: Small non-coding RNAs in diseases.

• DOI: 10.3389/fmolb.2022.1086768
• 发表时间: 2022
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5

Changes of Small Non-coding RNAs by Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

• DOI: 10.3389/fmolb.2022.821137
• 发表时间: 2022
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5
• 作者: Wu W;Choi EJ;Wang B;Zhang K;Adam A;Huang G;Tunkle L;Huang P;Goru R;Imirowicz I;Henry L;Lee I;Dong J;Wang T;Bao X
• 通讯作者: Bao X