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The Role of alternative mRNA polyadenylation in SARS-CoV-2 replication & the host response

替代 mRNA 多聚腺苷酸化在 SARS-CoV-2 复制中的作用

基本信息

批准号：
10559623
负责人：
CLAIRE L MOORE
金额：
$ 24.75万
依托单位：
TUFTS UNIVERSITY BOSTON
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：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10559623
关键词：
2019-nCoV A549 ACE2 Affect Antiviral Response Apoptosis Basic Science Biology COVID-19 COVID-19 pandemic COVID-19 patient Cell Cycle Cell Line Cell Nucleus Cell physiology Cells Chromatin Complex Cytomegalovirus Data Domestic Animals Enzyme-Linked Immunosorbent Assay Epithelial Cells Functional disorder Gene Expression Genes Genetic Transcription Genome Goals Herpesviridae Human Immune response Immunity In Vitro Individual Infection Inflammatory Response Influenza Innate Immune Response Integration Host Factors Knowledge Lead Learning Length Lung Maps Measures Mediating Messenger RNA Metabolism Molecular National Institute of Allergy and Infectious Disease Natural Immunity Nuclear Pathogenesis Pathogenicity Pathway interactions Peptide Signal Sequences Poly A Poly(A) Tail Polyadenylation Polyadenylation Pathway Positioning Attribute Process Proteins Proteomics Publishing RNA Reaction Recombinants Regulation Regulator Genes Research Research Priority Role SARS-CoV-2 infection SARS-CoV-2 transmission Site Strategic Planning Tail Testing Therapeutic Tissues Translating Translations Vesicular stomatitis Indiana virus Viral Viral Physiology Viral Proteins Virus Virus Diseases Virus Replication Wild Animals design experience mRNA Cleavage and Polyadenylation Factors mRNA Expression mRNA Precursor mRNA sequencing new therapeutic target overexpression polyadenylated messenger RNA posttranscriptional recruit severe COVID-19 transmission process vesicle transport viral RNA whole genome

项目摘要

Determining the role of alternative mRNA polyadenylation in SARS-Cov-2 replication and the host innate immune response SARS-CoV-2 infection has caused the COVID-19 pandemic, and understanding the molecular mechanisms leading to its pathophysiology is a top biomedical priority. In spite of intense research over the last year, we still have much to learn about host factors that promote or restrict SARS-CoV-2 infection and how manipulating them might enable new antiviral treatments. Changes within the infected cell are often mediated by changes in mRNA synthesis that affect not only transcription but also mRNA processing. mRNA precursor is cleaved at its 3’ end and a poly(A) tail added in a process called cleavage and polyadenylation (C/P). If C/P is blocked, mRNA is degraded, poorly exported from the nucleus, and poorly translated. Changing the poly(A) site position, or alternative polyadenylation (APA), affects the type and amount of protein produced from an mRNA. Many viruses have found ways to manipulate C/P and APA to promote viral replication, to interfere with the host antiviral response, or to hijack C/P proteins to augment viral activities. Several screens have demonstrated interaction of C/P proteins with SARS-Cov2 proteins and RNA and identified some C/P proteins as antiviral factors. However, it remains unknown whether SARS-CoV-2 causes changes in poly(A) site usage that support its replication and/or lead to the dysregulation of innate immunity that might contribute to the pathogenic inflammatory response seen in severe COVID-19 cases. By analyzing global pA site usage in cells infected with SARS-CoV-2 using published mRNA-seq data, we found that SARS-CoV-2 infection changes APA of genes involved in immunity, apoptosis, vesicle transport, metabolism, and cell cycle. Based on this preliminary observation, we hypothesize that alterations in C/P caused by SARS-CoV-2 infection influence viral replication and the host antiviral response. To investigate how SARS-CoV-2 affects C/P in host cells and whether targeting the C/P proteins might alter the progression of viral infection, we will 1) determine if C/P is inhibited across the genome during SARS- CoV-2 infection, 2) determine the effects of overexpressing or depleting C/P proteins that regulate APA, and 3) determine if specific viral proteins known to interact with C/P proteins affect 3' end processing. Successful completion of this study will determine if manipulation of C/P has potential as a novel therapeutic target for COVID-19.

确定选择性mRNA聚腺苷化在SARS-Cov-2复制和宿主中的作用