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Identification of Host Directed Drug Targets for SARS-CoV-2 Using Transposon Mutagenesis

使用转座子诱变鉴定 SARS-CoV-2 宿主定向药物靶点

基本信息

批准号：
10238213
负责人：
Anna Bruchez
金额：
$ 44.28万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-06 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238213
关键词：
2019-nCoV Address Antiviral Agents Bioinformatics COVID-19 pandemic Candidate Disease Gene Cell Death Cell Line Cells Coronavirus Country Data Development Disease Outbreaks Drug Targeting Ebola Elements Equilibrium Future Genes Genetic Genetic Screening Goals Health system High-Throughput Nucleotide Sequencing Host Defense Host Defense Mechanism Infection Infection prevention Influenza A virus Innate Immune System Integration Host Factors Laboratories Libraries Mediating Methodology Methods MicroRNAs Mutagenesis Nature Pathogenicity Pathway interactions Public Health RNA interference screen Resistance Resistance to infection SARS-CoV-2 infection Scientist Site Speed Therapeutic Therapeutic Intervention Transcript Untranslated RNA Up-Regulation Vesicular stomatitis Indiana virus Viral Virus Virus Diseases Virus Replication Work antiviral immunity base causal variant cell type falls gene interaction genetic approach genome-wide inhibitor/antagonist innovation insight mutant new therapeutic target novel novel therapeutics overexpression pandemic disease physiologic model prevent public health emergency resistance gene resistance mechanism screening spillover event targeted treatment therapeutic candidate therapeutic target viral resistance virus host interaction

项目摘要

SUMMARY The ongoing SARS-CoV-2 pandemic has brought into stark relief the need for novel therapeutics that can work against a broad spectrum of coronaviruses. Identifying essential host genes involved in both virus replication and antiviral defense could reveal key host-directed viral therapies that have the potential to work against SARS-CoV-2 and future coronavirus outbreaks. The overarching goal of our laboratory is to identify mechanisms of host defense against viral infections. This application aims to identify both host-encoded mechanisms of resistance to infection by SARS-CoV-2 as well as cellular factors critical for virus replication. Based on emerging data and our preliminary studies, our central hypothesis is that the up-regulation of host ‘restriction factors’ that prevent viral entry, constrain virus replication in host cells, or increase the ability of cells to withstand viral-induced cytopathy represent an important strategy in host defense. Our rationale for the proposed work is that identification of such factors will provide new targets for therapeutic intervention, and that these may be less susceptible to resistance than viral-encoded targets. We will use a novel forward-genetic approach to screen for host genes that confer resistance to SARS-CoV-2 infection in BSL3 using the native virus. This will allow us to identify key targets at all stages of virus infection. We will then validate new host targets and use these insights to rationally develop antiviral therapeutic strategies. Our screening approach is innovative because it allows identification of both host genes that confer resistance as well as host genes required for infection, which are normally detected in conventional RNAi-based screens. This work has the potential to identify new targets, including non-coding RNA elements, which would be missed using existing approaches.

总结持续的SARS-CoV-2大流行使人们对新疗法的需求得到了极大的缓解对抗广谱冠状病毒。确定参与病毒复制的必需宿主基因抗病毒防御可以揭示关键的宿主导向病毒疗法，这些疗法有可能对抗 SARS-CoV-2和未来的冠状病毒爆发。我们实验室的首要目标是确定宿主防御病毒感染的机制。此应用程序旨在识别主机编码的抗SARS-CoV-2感染的机制以及对病毒复制至关重要的细胞因子。基于新出现的数据和我们的初步研究，我们的中心假设是，宿主的上调 “限制因子”，阻止病毒进入，限制病毒在宿主细胞中的复制，或增加细胞的能力抵抗病毒诱导的细胞病变是宿主防御的重要策略。我们的理由是，拟议的工作是，这些因素的鉴定将为治疗干预提供新的靶点，这些可能比病毒编码的靶标更不易受耐药性的影响。我们将使用一种新的前向遗传一种使用天然的抗SARS-CoV-2抗体筛选BSL 3中赋予抗SARS-CoV-2感染的宿主基因的方法，病毒这将使我们能够识别病毒感染各个阶段的关键目标。然后，我们将验证新主机靶点，并利用这些见解来合理开发抗病毒治疗策略。我们的筛选方法是创新性在于它允许鉴定赋予抗性的宿主基因以及宿主基因这是感染所必需的，通常在传统的基于RNAi的筛选中检测到。这项工作有潜在的识别新的目标，包括非编码RNA元件，这将错过使用现有的接近。