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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.

摘要 2019年冠状病毒病（COVID-19）是由人类冠状病毒SARS-CoV-2引起的。这种病毒导致中国大规模疫情爆发，人与人之间的传播率和死亡率很高随后导致了人类的大流行。SARS-CoV-2是一种新型冠状病毒，与SARS冠状病毒高度相关。在一场持续的进化军备竞赛中，病毒进化出了促进病毒进化的因素它们的复制，而宿主细胞已经进化出信号网络来检测和消灭入侵的病毒。的先天免疫系统是一种保守的防御策略，对于病原体的初始检测和限制至关重要然后激活适应性免疫反应。先天免疫的激活依赖于对病原体相关的分子模式（PAMP）通过模式识别受体（PRR），如Toll样受体、RNA和DNA传感器。在被PAMP激活后，PRR募集启动信号传导的衔接蛋白，涉及修饰酶的途径，如激酶、磷酸酶、E3泛素连接酶，包括IRF 3和NF-κ B在内的关键转录因子的激活。这些因素协同作用，抗病毒I型干扰素（IFN-I）的产生、炎性细胞因子、NK细胞免疫、细胞凋亡和自噬因此，病毒在宿主中的致病性和传播性部分取决于病毒的能力来逃避宿主细胞的先天反应SARS-CoV-2病毒粒子具有三种跨膜蛋白[包膜（E），膜（M）和刺突（S）]，这些是病毒组装和感染性所必需的。他们也有重要的免疫调节功能，因为它们触发或拮抗感染细胞内的先天免疫应答。的来自其他冠状病毒的E蛋白已被证明形成具有离子通道活性的寡聚体结构，可以改变钙稳态，并暗示病毒的发病机制。其他冠状病毒的M蛋白是显示通过TLR依赖性和非依赖性机制具有一系列免疫调节作用， S蛋白可通过调节表面信号应答发挥其作用。它也会导致 BST-2（系链蛋白），其功能是防止子代病毒的释放。我们假设 SARS-CoV-2膜蛋白的免疫调节特性将决定感染和病毒介导的发病机制。为了验证这一点，在目标1中，我们建议检查E，M和S蛋白从SARS-CoV-2，并比较它们在调节先天免疫，促炎反应，自噬和凋亡与SARS-CoV、MERS-CoV和HCoV-OC 43的相同蛋白。在目标2中，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的免疫逃避能力，并比较它们与SARS-CoV、MERS和HCoV-OC 43一起感染。总的来说，这些研究的结果将进一步加深我们对人类冠状病毒的免疫逃避策略，并指导有效疫苗的开发。