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.

项目概要/摘要严重急性呼吸综合征冠状病毒 2 (SARS-CoV2) 感染会导致冠状病毒病 2019（COVID-19），其特征是肺部和其他器官（例如肺部）的急性炎症心脏和肠道。越来越清楚的是，SARS-CoV2 的发病机制涉及抑制抗病毒先天免疫和诱导炎症反应。 SARS-CoV2 抑制诱导抗病毒 I 型干扰素 (IFN)，从而避免早期抗病毒免疫的破坏。随后引发的炎症反应推动了 COVID-19 的发展。了解如何 SARS-CoV2 抑制 I 型 IFN 表达并诱导炎症反应，对于设计至关重要治疗方法。基于对 SARS-CoV（SARS-CoV2 的密切同源物）的研究，几种病毒蛋白质与宿主免疫系统的相互作用有关，有助于抑制类型 I 干扰素反应和促炎细胞因子的诱导。本补充申请的主要目标目的是了解 SARS-CoV2 蛋白抑制抗病毒先天免疫的机制，以及刺激加剧的炎症反应。我们将实现两个具体目标。在具体目标 1 中，我们将研究 SARS-CoV2 蛋白如何抑制 TBK1 信号传导和先天抗病毒作用免疫。如母基金所述，TBK1 是一种激酶，可响应来自 toll 样信号的信号病毒感染期间的受体（TLR）和其他模式识别受体（PRR）并介导诱导 I 型干扰素。同时，TBK1 负向调节促炎细胞因子的诱导，以防止加剧炎症。我们的家长资助重点是阐明 TBK1 如何调节 TLR 信号传导以及肠道微生物引起的肠道炎症。在此补充申请中，我们将特别解决 SARS-CoV2 蛋白如何调节 TBK1 信号传导以抑制抗病毒免疫和刺激炎症。我们将检验我们的假设，即 SARS 抑制 TBK1 信号传导 CoV2蛋白不仅抑制I型干扰素的产生，还促进炎症反应。在具体目标 2 中，我们将系统地定义 SARS-COV2 蛋白诱导的机制使用细胞培养物和小鼠模型研究炎症反应。我们将检查信号通路参与 SARS-CoV2 诱导的巨噬细胞和上皮细胞中促炎细胞因子的表达。我们还将研究 SARS-CoV2 的刺突蛋白如何下调其细胞受体血管紧张素- 转换酶 2 (ACE2)。由于 ACE2 是一种关键的抗炎因子，我们假设 Spike 蛋白质诱导的 ACE2 下调对肺部和肠道炎症的诱导至关重要。我们相信这些拟议的研究解决了介导疾病发病机制的新机制 COVID19 将对 COVID19 治疗产生重要影响。