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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