Immunomodulatory effects of coronavirus membrane proteins E, M, and S.

冠状病毒膜蛋白 E、M 和 S 的免疫调节作用。

基本信息

批准号：
10178404
负责人：
Maria Kalamvoki
金额：
$ 42.08万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
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：
2020-08-17 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10178404
关键词：
2019-nCoV Adaptor Signaling Protein Affect Antiviral Agents Apoptosis Autophagocytosis Biological Assay Bone Marrow COVID-19 COVID-19 pandemic Calcium Cell physiology Cells Cellular Structures China Common Cold Coronavirus Custom DNA Detection Development Disease Outbreaks Endothelial Cells Enzymes Epithelial Cells Fibroblasts Gene Expression Generations Genes Homeostasis Human Human Activities IRF3 gene Immune response Immunity Infection Inflammation Inflammatory Innate Immune Response Innate Immune System Integral Membrane Protein Interferon Type I Interferons Invaded Ion Channel Knowledge Lead Link Lung Mediating Membrane Membrane Proteins Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Modification Molecular Monitor Morbidity - disease rate Morphogenesis Natural Immunity Natural Killer Cells Nucleotides Outcome Pathogenesis Pathogenicity Pathway interactions Pattern Pattern recognition receptor Phosphoric Monoester Hydrolases Phosphotransferases Population Production Property Proteins RNA Race Reporting Role SARS coronavirus Severe Acute Respiratory Syndrome Signal Pathway Signal Transduction Specificity Structural Protein Structure Surface Testing Toll-like receptors Vaccines Viral Viral Pathogenesis Viral Proteins Virion Virus Virus Assembly Virus-like particle adaptive immune response airway epithelium arm biological adaptation to stress cell type cytokine env Gene Products gene function human coronavirus immunoregulation insight macrophage member mortality novel therapeutics pandemic disease particle particle exposure pathogen pathogenic virus prevent recruit response sensor stem transcription factor transmission process ubiquitin-protein ligase vaccine development

项目摘要

ABSTRACT COronaVIrus Disease 2019 (COVID-19) is caused by a human coronavirus, SARS-CoV-2. This virus caused a large outbreak in China that was associated with a high human-to-human transmission rate and mortality and subsequently led to a pandemic in the human population. SARS-CoV-2 is member of the â-coronaviruses and is highly related to SARS-CoV. In an ongoing evolutionary arms race, viruses have evolved factors that facilitate their replication while the host cell has evolved signaling networks to detect and eradicate invading viruses. The innate immune system is a conserved defense strategy critical for the initial detection and restriction of pathogens and later activation of the adaptive immune response. Activation of innate immunity relies on the recognition of pathogen-associated molecular patterns (PAMP) by pattern recognition receptors (PRRs) such as Toll-like receptors, RNA and DNA sensors. Upon activation by PAMPs, PRRs recruit adaptor proteins that initiate signaling pathways involving modifying enzymes such as kinases, phosphatases, E3 ubiquitin ligases that ultimately lead to the activation of crucial transcription factors including IRF3 and NF-êB. Synergistically, these factors promote the production of antiviral type I interferons (IFN-I), inflammatory cytokines, NK cell immunity, apoptosis, and autophagy. Thus, the pathogenicity and spread of a virus in the host is in part determined by the ability of the virus to evade host cell innate responses. The SARS-CoV-2 virion has three transmembrane proteins [envelope (E), membrane (M), and spike (S)] that are necessary for viral assembly and infectivity. They also have important immunomodulatory functions as they trigger or antagonize innate immune responses within infected cells. The E proteins from other coronaviruses have been shown to form an oligomeric structure with ion channel activity that can alter calcium homeostasis with implications on viral pathogenesis. The M protein of other coronaviruses was shown to have a range of immunomodulatory effects through TLR-dependent and independent mechanisms and the S protein can exert its effects by modulating surface signaling responses. It also causes the degradation of BST-2 (tetherin), which functions to prevent release of progeny virus. We hypothesize that the immunomodulatory properties of SARS-CoV-2 membrane proteins will determine the outcome of the infection and viral mediated pathogenesis. To test this, in Aim 1, we propose to examine E, M, and S proteins from SARS-CoV-2 and compare their impact in modulating innate immunity, proinflammatory responses, autophagy, and apoptosis with the same proteins from SARS-CoV, MERS-CoV, and HCoV-OC43. In Aim 2, we will determine the immunomodulatory effects of virus-like particles (VLPs) formed by the membrane proteins of the four viruses. We will also determine the immunoevasion capabilities of of SARS-CoV-2 and compare them with SARS-CoV, MERS and HCoV-OC43. Overall, the results of these studies will further our knowledge of immunoevasion strategies of human coronaviruses and guide in the development of efficacious vaccines.

抽象的 2019年冠状病毒病（COVID-19）是由人类冠状病毒SARS-COV-2引起的。该病毒在中国引起了很大的爆发，与人类到人类的传播率和死亡率高有关随后导致人口大流行。 SARS-COV-2是 - 核心病毒和与SARS-COV高度相关。在正在进行的进化武器竞赛中，病毒已经发展为促进的因素它们的复制在宿主细胞已经发展为信号网络以检测和放射性入侵病毒。先天免疫系统是一种构成的防御策略，对于初始检测和病原体的限制至关重要后来激活自适应免疫响应。识别先天免疫的激活通过模式识别受体（PRR），例如Toll-like，与病原体相关的分子模式（PAMP）受体，RNA和DNA传感器。 PAMP激活后，PRRS募集了启动信号传导的适配器蛋白涉及修饰酶的途径，例如激酶，磷酸酶，E3泛素连接酶，最终导致激活包括IRF3和NF-êb在内的关键转录因子。从协同上讲，这些因素促进 I型I型干扰素（IFN-I），炎性细胞因子，NK细胞免疫，凋亡和凋亡的产生自噬。这就是病毒在宿主中的致病性和扩散部分取决于病毒的能力逃避宿主细胞先天反应。 SARS-COV-2病毒体具有三种跨膜蛋白[包膜（E），，膜（M）和尖峰（S）]是病毒组装和感染所必需的。他们也很重要免疫调节功能触发或拮抗感染细胞内的先天免疫反应。这已证明来自其他冠状病毒的E蛋白质形成具有离子通道活性的寡聚结构可以改变钙稳态，对病毒发病机理产生影响。其他冠状病毒的M蛋白是证明通过TLR依赖和独立机制具有一系列免疫调节作用， S蛋白可以通过调节表面信号反应来执行其效果。这也导致降解 BST-2（Tetherin），该功能可防止释放后代病毒。我们假设 SARS-COV-2膜蛋白的免疫调节特性将确定感染和病毒介导的发病机理。为了测试这一点，在AIM 1中，我们建议检查E，M和S蛋白从SARS-COV-2开始，并比较它们在调节先天免疫，促炎反应的影响，来自SARS-COV，MERS-COV和HCOV-OC43的相同蛋白质的自噬和凋亡。在AIM 2中，我们将确定由膜蛋白形成的病毒样颗粒（VLP）的免疫调节作用四种病毒。我们还将确定SARS-COV-2的免疫避免能力并进行比较使用SARS-COV，MERS和HCOV-OC43。总体而言，这些研究的结果将进一步我们对人类冠状病毒的免疫避难策略和指导有效疫苗的开发。