Molecular mechanisms underlying immunosuppression and inflammation caused by SARS-CoV2 proteins

SARS-CoV2蛋白引起免疫抑制和炎症的分子机制

基本信息

批准号：
10163402
负责人：
Shao-Cong Sun
金额：
$ 16.29万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2020-08-21 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163402
关键词：
2019-nCoV A549 Acute Address Agonist Anti-Inflammatory Agents Antiviral Agents Antiviral Therapy Applications Grants Binding Biological Assay COVID-19 Cell Culture Techniques Cells Coronavirus Detection Development Down-Regulation Enzyme-Linked Immunosorbent Assay Epithelial Cells Event Genes Goals Grant Heart Homologous Gene Host Defense Human Human Cell Line IRF3 gene Imiquimod Immune Immune response Immune system Immunosuppression Infection Inflammation Inflammatory Response Innate Immune System Interferon Type I Interferons Intestines Invaded Knowledge Lung Lung Inflammation Mass Spectrum Analysis Measures Mediating Membrane Proteins Messenger RNA Molecular Natural Immunity Nucleocapsid Proteins Organ Pathogenesis Pathogenicity Pathway interactions Pattern recognition receptor Peptidyl-Dipeptidase A Phase Phosphorylation Phosphotransferases Play Polymerase Chain Reaction Production Protein Kinase Proteins RNA Receptor Signaling Reporting Research Reverse Transcription Role SARS coronavirus Sendai virus Serine Signal Pathway Signal Transduction Structural Protein TBK1 gene TLR3 gene TLR7 gene TNF receptor-associated factor 3 Testing The Sun Therapeutic Time Toll-like receptors Tretinoin Ubiquitination Viral Viral Proteins Viral Structural Proteins Virus Virus Diseases activating transcription factor antiviral immunity base casein kinase II cytokine design expression vector gene induction gut microbes inflammatory disease of the intestine innate immune mechanisms innovation knock-down macrophage monocyte mouse model novel parent grant prevent protein function receptor recruit response screening vector

项目摘要

PROJECT SUMMARY/ABSTRACT Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) causes coronavirus disease 2019 (COVID-19), which is characterized by acute inflammation in the lung and other organs, such as the heart and intestine. It is increasingly clear that the pathogenesis of SARS-CoV2 involves suppression of antiviral innate immunity and induction of inflammatory responses. SARS-CoV2 suppresses induction of the antiviral type I interferons (IFNs) and, thereby, escapes from destruction by the early phase antiviral immunity. Subsequent induction of inflammatory responses drives the development of COVID-19. Understanding how SARS-CoV2 suppresses type I IFN expression and induces inflammatory responses, is crucial for designing therapeutic approaches. Based on the studies of SARS-CoV, the close homolog of SARS-CoV2, several viral proteins have been implicated in the interplay with host immune system, contributing to the suppression of type I IFN responses and induction of proinflammatory cytokines. The major goal of this supplementary application is to understand the mechanisms by which SARS-CoV2 proteins suppress antiviral innate immunity and stimulate exacerbated inflammatory responses. We will perform two specific aims. In Specific Aim 1, we will examine how SARS-CoV2 proteins suppress TBK1 signaling and antiviral innate immunity. As described in the parent grant, TBK1 is a kinase that responds to signals from the toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) during viral infections and mediates induction type I IFNs. At the same time, TBK1 negatively regulates proinflammatory cytokine induction to prevent exacerbated inflammation. Our parental grant focuses on the elucidation of how TBK1 regulates TLR signaling and intestinal inflammation caused by gut microbes. In this supplementary application, we will specifically address how SARS-CoV2 proteins modulate TBK1 signaling in the suppression of antiviral immunity and stimulation of inflammation. We will examine our hypothesis that suppression of TBK1 signaling by SARS- CoV2 proteins not only inhibits type I IFN production but also promotes inflammatory responses. In Specific Aim 2, we will systematically define the mechanisms by which SARS-COV2 proteins induce inflammatory responses using both cell culture and mouse models. We will examine the signaling pathways involved in SARS-CoV2-induced expression of proinflammatory cytokines in macrophages and epithelial cells. We will also examine how the Spike protein of SARS-CoV2 downregulates its cellular receptor, angiotensin- converting enzyme 2 (ACE2). Since ACE2 is a pivotal anti-inflammatory factor, we hypothesize that Spike protein-induced ACE2 downregulation critically contributes to the induction of lung and intestinal inflammation. We believe that these proposed studies address novel mechanisms that mediate the pathogenesis of COVID19 and will have important implications for COVID19 therapies.

项目摘要/摘要严重急性呼吸道综合征冠状病毒2（SARS-COV2）感染导致冠状病毒病 2019年（COVID-19），其特征是肺部和其他器官中的急性炎症，例如心脏和肠。越来越明显的是，SARS-COV2的发病机理涉及抑制抗病毒先天免疫力和炎症反应的诱导。 SARS-COV2抑制了 I型I型干扰素（IFN），从而通过早期抗病毒免疫逃脱了破坏。随后的炎症反应诱导驱动了COVID-19的发展。了解如何 SARS-COV2抑制I型IFN表达并引起炎症反应，对于设计至关重要治疗方法。基于SARS-COV的研究，SARS-COV2的近距离同源物，几种病毒蛋白质已与宿主免疫系统相互作用，有助于抑制类型 I IFN反应和促炎细胞因子的诱导。此补充应用的主要目标是要了解SARS-COV2蛋白抑制抗病毒先天免疫和的机制刺激恶化的炎症反应。我们将执行两个具体的目标。在特定目标1中，我们将研究SARS-COV2蛋白如何抑制TBK1信号传导和抗病毒先天免疫。如父授予赠款中所述，TBK1是一种激酶，它响应类似收费的信号病毒感染期间受体（TLR）和其他模式识别受体（PRR）并介导诱导 I型IFNS。同时，TBK1负调节促炎细胞因子诱导以防止恶化的炎症。我们的父母赠款重点是阐明TBK1如何调节TLR信号传导和由肠道微生物引起的肠炎。在此补充应用中，我们将特别解决SARS-COV2蛋白如何调节抗病毒免疫抑制和刺激炎症。我们将研究我们的假设，即SARS-抑制TBK1信号传导 COV2蛋白不仅抑制I型IFN产生，而且促进炎症反应。在特定目标2中，我们将系统地定义SARS-COV2蛋白的机制使用细胞培养和小鼠模型进行炎症反应。我们将检查信号通路参与巨噬细胞和上皮细胞中SARS-COV2诱导的促炎细胞因子的表达。我们还将研究SARS-COV2的尖峰蛋白如何下调其细胞受体血管紧张素 - 转换酶2（ACE2）。由于ACE2是一个关键的抗炎因子，因此我们假设Spike 蛋白质诱导的ACE2下调严重有助于诱导肺部和肠炎。我们认为，这些提出的研究涉及介导的新机制 Covid19，将对Covid19疗法具有重要意义。