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）及其严重的药物严重的急性呼吸道综合征2（SARS-COV-2）目前是最紧迫的健康问题。需要了解有关病毒的病理以及对病毒感染的宿主反应的更多信息。急性呼吸窘迫综合征（ARDS）是严重的Covid-19的最终状态，是由宿主无法控制的免疫反应引起的，所谓的细胞因子释放综合征（CRS）。易于某些患者发展到严重的Covid-19的原因尚不清楚，但是某些人群（例如老年患者和癌症患者）的风险更高。因此，我们正在研究宿主microRNA（miRNA）是否可以用作COVID-19的预后生物标志物。由于miRNA几乎调节了每个细胞过程，并且在疾病中通常会失调，包括病毒感染，因此SARS-COV-2感染很可能会影响miRNA水平。已知在病毒感染期间的异常miRNA特征既是由宿主反应来抵消感染剂的反应和病毒的故意作用引起的，通常是为了抑制我们的小组对某些疱疹病毒转录物选择性地结合宿主miRNA和在靶向靶向的过程中降级的降解，从而使某些疱疹病毒转录的认识大大贡献了这一贡献。选择性miRNA降解对病毒是有益的，例如，宿主miR 27a的水平降低，导致T细胞激活长期，这有助于Saimiri的致癌性转化。 SARS-COV-2有可能选择性地影响调节关键细胞因子的miRNA，因为已知许多miRNA都可以调节抗病毒防御中涉及的免疫因子。其中之一是在严重的Covid19：白介素6（IL-6）期间的关键参与者，由miR-146a，mir-142-3p和let-7调节。因此，记录SARS-COV-2感染过程中特定miRNA的失调可能具有治疗潜力，并为共同进展提供生物标志物。我们将使用最先进的RNA测序，以及Taqman逆转录定量PCR（RT-QPCR）检测RNA，在感染了具有SARS-COV-2的几种肺细胞系后，在不同时间研究miRNA种群。此外，我们正在使用自定义的生物信息学预测来搜索可以选择性调节宿主miRNA并已经确定了几个潜在候选者的病毒转录本。关注这些重要的宿主非编码RNA的基本见解对人类管理当前和未来大流行的能力对这些重要的宿主非编码RNA非常重要。

项目成果

期刊论文数量（295）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Vesicular trafficking of incoming human papillomavirus 16 to the Golgi apparatus and endoplasmic reticulum requires γ-secretase activity.

DOI：
10.1128/mbio.01777-14
发表时间：
2014-09-16
期刊：
mBio
影响因子：
6.4
作者：
Zhang W;Kazakov T;Popa A;DiMaio D
通讯作者：
DiMaio D

Efficient induction of nuclear aggresomes by specific single missense mutations in the DNA-binding domain of a viral AP-1 homolog.

通过病毒 AP-1 同源物 DNA 结合域中的特定单错义突变有效诱导核聚集体。

DOI：
10.1074/jbc.m110.198325
发表时间：
2011
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Park,Richard;Wang'ondu,Ruth;Heston,Lee;Shedd,Duane;Miller,George
通讯作者：
Miller,George

The interaction of a topoisomerase-like enzyme from herpes simplex virus type 1-infected cells with non-viral circular DNA.

来自 1 型单纯疱疹病毒感染细胞的拓扑异构酶样酶与非病毒环状 DNA 的相互作用。

DOI：
10.1099/0022-1317-65-8-1341
发表时间：
1984
期刊：
The Journal of general virology
影响因子：
0
作者：
Leary,K;Francke,B
通讯作者：
Francke,B

Limitations to the expression of parvoviral nonstructural proteins may determine the extent of sensitization of EJ-ras-transformed rat cells to minute virus of mice.

细小病毒非结构蛋白表达的限制可能决定EJ-ras转化的大鼠细胞对小鼠微小病毒的敏感性程度。

DOI：
10.1016/0042-6822(89)90514-x
发表时间：
1989
期刊：
Virology
影响因子：
3.7
作者：
VanHille,B;Duponchel,N;Salomé,N;Spruyt,N;Cotmore,SF;Tattersall,P;Cornelis,JJ;Rommelaere,J
通讯作者：
Rommelaere,J

Infectious mononucleosis: a polyclonal B cell transformation in vivo.

传染性单核细胞增多症：体内多克隆 B 细胞转化。