Next Generation Resolution of Antiviral Gene Networks

抗病毒基因网络的下一代解决方案

基本信息

批准号：
10267768
负责人：
Dusan Bogunovic
金额：
$ 66.2万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2020-09-22 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10267768
关键词：
Address Antiviral Agents Antiviral Therapy Biological Assay COVID-19 outbreak Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collection Communicable Diseases Communication Complex Cytometry DNA Viruses Data Epithelial Cells Feedback Fibroblasts Gene Expression Profile Genes Growth Herpesvirus 1 Host Defense Human ISG15 gene Immune Individual Infection Influenza A virus Inherited Interferon Type I Interferons JAK1 gene Journals Laboratories Laboratory Study Mediating Mediator of activation protein Memory Nature Pathogenicity Peripheral Blood Mononuclear Cell Phenotype Physiological Predisposition Proteins RNA Viruses Refractory Regulation Resistance Resolution Sampling Secondary to Signal Transduction Syndrome System Techniques Technology Testing Therapeutic Time Toxic effect Vaccination Vesicular stomatitis Indiana virus Viral Virus Virus Diseases Work Yellow Fever Zika Virus airway epithelium antiviral immunity cell type combinatorial experimental study gene function high dimensionality human model imprint in vitro Model in vivo new technology next generation novel pandemic disease pathogenic virus programs respiratory pathogen response side effect single-cell RNA sequencing

项目摘要

SUMMARY As the primary mediators of the innate response to viral infection, type I interferons (IFN-I) establish an antiviral state in both infected and uninfected bystander cells through the induction of several hundreds of interferon stimulated genes (ISGs). The mechanisms by which the coordinated activities of these ISGs confer resistance to diverse viruses, and the regulatory circuits that modulate their expression remain poorly understood. Working with unique samples from individuals with hereditary syndromes of dysregulated IFN-I responsiveness, we have identified a collection of thirty ISGs that confer resistance to diverse viruses (increased protection against RNA and DNA viruses with both high and low pathogenic burden). We have also uncovered previously unappreciated negative feedback mechanisms of IFN-I signaling. We have found that these regulatory circuits, as well as ISG expression patterns, vary significantly across different cell types at steady state and upon IFN-I stimulation. Recent technological advances now enable us to explore these cooperative ISG antiviral functions and negative feedback mechanisms at unprecedented depth and resolution. In the studies proposed here, we will identify subsets of ISGs sufficient to confer broad protection against multiple viruses using a novel single cell RNA-Seq strategy. This approach provides the throughput required to conduct complex combinatorial experiments while maintaining the high resolution to test specific hypotheses. Results may offer new broad spectrum antiviral therapeutic strategies, which would be of particular value against emerging viral pathogens. We will also investigate in detail the mechanisms by which IFN-I signaling establishes a lasting imprint on cellular responsiveness to subsequent IFN-I stimulation. This recently described but incompletely characterized phenomenon likely has important implications for successive infectious challenges and viral susceptibilities. Combining a unique collection of clinical samples, cutting edge technologies, and diverse and complementary expertise in immunovirology from our two laboratories, these studies are expected to address long standing, fundamental questions in innate antiviral immunity, as well as to pioneer new directions for developing antiviral therapies.

概括作为对病毒感染的先天反应的主要介质，I 型干扰素 (IFN-I) 建立了抗病毒作用通过诱导数百种干扰素，在受感染和未受感染的旁观者细胞中形成状态刺激基因（ISG）。这些 ISG 的协调活动赋予抵抗力的机制对于不同的病毒，调节其表达的调节回路仍然知之甚少。在职的通过来自患有 IFN-I 反应失调遗传性综合征的个体的独特样本，我们确定了 30 个 ISG 的集合，这些 ISG 赋予对多种病毒的抵抗力（增强对 RNA 的保护）以及具有高和低致病负荷的 DNA 病毒）。我们还发现了以前未被重视的 IFN-I信号传导的负反馈机制。我们发现这些调节电路以及ISG 在稳态和 IFN-I 刺激下，不同细胞类型的表达模式存在显着差异。最近的技术进步现在使我们能够探索这些合作的 ISG 抗病毒功能和负面影响反馈机制具有前所未有的深度和分辨率。在这里提出的研究中，我们将确定 ISG 的子集，足以提供针对多种病毒的广泛保护。使用新型单细胞 RNA-Seq 策略的病毒。这种方法提供了进行所需的吞吐量复杂的组合实验，同时保持高分辨率来测试特定假设。结果可能提供新的广谱抗病毒治疗策略，这对于对抗病毒具有特别价值新出现的病毒病原体。我们还将详细研究 IFN-I 信号传导建立的机制对随后的 IFN-I 刺激的细胞反应产生持久的影响。最近描述了这一点，但是不完全表征的现象可能对连续的感染挑战具有重要影响和病毒敏感性。结合了独特的临床样本集合、尖端技术和我们两个实验室在免疫病毒学方面具有多样化和互补的专业知识，预计这些研究解决先天抗病毒免疫中长期存在的基本问题，并开拓新方向用于开发抗病毒疗法。