Molecular Basis of Cancer Virus Replication, Transformation, and Innate Defense

癌症病毒复制、转化和先天防御的分子基础

基本信息

批准号：
10158926
负责人：
Daniel C. Dimaio
金额：
$ 5.58万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10158926
关键词：
2019-nCoV Administrative Supplement Adopted Adult Respiratory Distress Syndrome Affect Antiviral Agents B-Lymphocytes Binding Biochemical Biogenesis Bioinformatics Biological Assay Biological Markers Biology COVID-19 Callithrix Cancer Patient Cell Line Cell Nucleus Cell Proliferation Cell physiology Cells Cleaved cell Collaborations Complex Custom Detection Development Disease Elements Episome Epstein-Barr Virus latency Epstein-Barr virus encoded RNA 1 Epstein-Barr virus encoded RNA 2 Funding Future Gene Expression Genetic Transcription Health Herpesviridae High-Throughput Nucleotide Sequencing High-Throughput RNA Sequencing Human Human Herpesvirus 4 Human Herpesvirus 8 Image Immune Evasion Immune response Immune system Immunologic Factors Immunoprecipitation In Situ Infection Interleukin-6 Introns Knock-out Length Ligation Lung Lymphoid Cell Lytic Lytic Phase MALAT1 gene Malignant Neoplasms Messenger RNA Methods MicroRNAs Molecular Nature Nuclear Nuclear Envelope Nuclear RNA Oncogenic Open Reading Frames PAX5 gene Pathology Pathway interactions Patients Poly A Poly(A) Tail Population Primates Process Proteins Psoralens RNA RNA-Protein Interaction Research Research Project Grants Reverse Transcription Rhadinovirus Rhesus Role Saimiriine Herpesvirus 2 Sequence Alignment Severity of illness Small Nuclear RNA Small RNA T-Cell Activation T-Lymphocyte Terminal Repeat Sequences Testing Therapeutic Time Transcript Transmission Electron Microscopy Untranslated RNA Viral Virus Virus Diseases Virus Replication capture hybridization analysis of RNA targets coronavirus disease crosslink crosslinking and immunoprecipitation sequencing cytokine cytokine release syndrome fighting follow-up gammaherpesvirus high risk in vitro activity in vivo insight nucleocytoplasmic transport older patient outcome forecast pandemic disease parent grant potential biomarker ribosome profiling synergism targeted treatment transcription factor transcriptome sequencing triple helix virtual

项目摘要

Coronavirus disease (COVID-19) and its causative agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently a most pressing health concern. Much more needs to be learned about the pathology of the virus, as well as the host response to viral infection. Acute respiratory distress syndrome (ARDS), the final state of severe COVID-19, is caused by the uncontrollable immune response of the host, so called cytokine release syndrome (CRS). What predisposes some patients to progress to severe COVID-19 is not known, but certain populations – such as the elderly and cancer patients – are at higher risk. Therefore, we are investigating whether host microRNAs (miRNAs) can serve as biomarkers for COVID-19 prognosis. Since miRNAs regulate virtually every cellular process, and are often dysregulated during disease, including viral infections, it is highly likely that SARS-CoV-2 infection impacts miRNA levels. Aberrant miRNA profiles during viral infection are known to be caused both by host responses to counteract the infecting agent and by deliberate actions of the virus, usually to dampen the immune system Our group has contributed significantly to the realization that some herpesviral transcripts selectively bind host miRNAs and induce their degradation in a process known as target-directed miRNA degradation (TDMD). Such selective miRNA degradation is beneficial for the virus, as exemplified by decreased levels of host miR 27a causing prolonged T cell activation that aids oncogenic transformation by herpesvirus saimiri. It is possible that SARS-CoV-2 selectively affects the miRNAs that regulate crucial cytokines, as many miRNAs are known to regulate immune factors involved in antiviral defense. One of these is a key player during severe COVID19: interleukin 6 (IL-6), which is regulated by miR-146a, miR-142-3p and let-7. Documenting the dysregulation of particular miRNAs during infection by SARS-CoV-2 can therefore have therapeutic potential, as well as providing biomarkers for COVID progression. We will use state-of-the art small RNA sequencing, as well as RNA detection by TaqMan reverse transcription quantitative PCR (RT-qPCR) to investigate miRNA populations at various times after infection of several lung cell lines with SARS-CoV-2. In addition, we are employing custom bioinformatic predictions to search for viral transcripts that could selectively regulate host miRNAs and have already identified several potential candidates. Providing fundamental insights into the biology of SARS-CoV-2 as regards these important host noncoding RNAs will be important for mankind’s ability to manage both the current and future pandemics.

冠状病毒病 (COVID-19) 及其病原体严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 是目前最紧迫的健康问题，需要更多地了解该病毒的病理学以及宿主。急性呼吸窘迫综合征 (ARDS) 是严重 COVID-19 的最终状态，是由宿主无法控制的免疫反应引起的，即所谓的细胞因子释放综合征 (CRS)，这使得一些患者容易发展为重症。 COVID-19 尚不清楚，但某些人群（例如老年人和癌症患者）的风险较高，因此，我们正在研究宿主 microRNA (miRNA) 是否可以作为 COVID-19 预后的生物标志物，因为 miRNA 几乎可以调节所有疾病。病毒感染期间的异常 miRNA 谱很可能是由宿主抵抗感染的反应引起的。我们的团队在认识到一些疱疹病毒转录物选择性结合宿主 miRNA 并在称为靶向 miRNA 选择性降解 (TDMD) 的过程中诱导其降解方面做出了重大贡献。 miRNA 降解对病毒有益，例如宿主 miR 27a 水平降低，导致 T 细胞活化延长，从而有助于疱疹病毒 saimiri 的致癌转化。选择性地影响调节关键细胞因子的 miRNA，因为已知许多 miRNA 可以调节参与抗病毒防御的免疫因子，其中之一是严重 COVID19 期间的关键参与者：白细胞介素 6 (IL-6)，它受 miR-146a 调节。因此，记录 SARS-CoV-2 感染过程中特定 miRNA 的失调具有治疗潜力，并为 COVID 进展提供生物标志物。将使用最先进的小 RNA 测序以及通过 TaqMan 逆转录定量 PCR (RT-qPCR) 进行的 RNA 检测来研究 SARS-CoV-2 感染几种肺细胞系后不同时间的 miRNA 群体。此外，我们正在采用定制的生物信息学预测来搜索可以选择性调节宿主 miRNA 的病毒转录本，并已经确定了几个潜在的候选者，为 SARS-CoV-2 的生物学提供关于这些重要宿主非编码 RNA 的基本见解。对于人类应对当前和未来流行病的能力非常重要。