Immunoproteasome-Mediated Inflammation in Coronavirus Respiratory Infection

冠状病毒呼吸道感染中免疫蛋白酶体介导的炎症

基本信息

批准号：
10622572
负责人：
Jason Brice Weinberg
金额：
$ 19.5万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-16 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622572
关键词：
2019-nCoV Acute Address Adrenal Cortex Hormones Adult Affect Age Alveolar Macrophages Animal Model Anti-Inflammatory Agents B-Lymphocytes Body Weight decreased CD8-Positive T-Lymphocytes COVID-19 COVID-19 pandemic Cells Child Classification Clinical Coronavirus Coronavirus Infections Data Development Disease Epitopes Goals Immune Immune response In Vitro Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Innate Immune Response Integration Host Factors Interferon Type II Knowledge Life Link Literature Lung MHC Class I Genes Macrophage Measures Mediating Mediator Morbidity - disease rate Mouse Strains Murine hepatitis virus Mus Organ Outcome Pathogenesis Pathology Pathway interactions Patient Selection Persons Play Population Predisposition Process Production Publishing Pulmonary Pathology Regulation Research Respiratory Tract Infections Role SARS-CoV-2 infection SARS-CoV-2 pathogenesis Signal Transduction Structure of parenchyma of lung System T cell response T-Lymphocyte Testing Therapeutic Ubiquitin Virus Virus Diseases Virus Replication Work World Health Organization acute infection age related animal coronavirus chemokine coronavirus disease cytokine cytokine release syndrome defined contribution human coronavirus immune function immune modulating agents immunopathology improved improved outcome in vivo mortality mouse model multicatalytic endopeptidase complex multiorgan damage neutrophil novel pandemic disease patient population pharmacologic respiratory response severe COVID-19 systemic inflammatory response

项目摘要

PROJECT SUMMARY Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus that has caused the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 is associated with severe, frequently life-threatening respiratory illness in a substantial proportion of affected people. Severe COVID-19 is characterized by an exuberant systemic inflammatory response to SARS-CoV-2 infection. That response aids in control of viral replication during acute infection, but it also drives virus-induced pathology and disease manifestations. For reasons that remain incompletely understood, that deleterious inflammatory response is less likely to develop in children infected with SARS-CoV-2, and children are more likely than adults to have asymptomatic infection or mild disease. The immunoproteasome (IP), an inducible component of the ubiquitin- proteasome system, is more efficient than the constitutive proteasome in generating MHC class I epitopes for recognition by CD8 T cells. IP activity also exerts intrinsic effects on T cell, B cell, macrophage, and DC functions and contributes to inflammatory responses via mechanisms that include degradation of IκB and subsequent activation of NF-κB-mediated inflammatory pathways. No studies have addressed contributions of the IP to the pathogenesis of human or animal coronaviruses. Our published and preliminary data suggest that IP subunit activity is developmentally regulated in the lungs and other organs, increasing with age. IP subunit expression increases in mice during acute infection with a murine coronavirus, and IP inhibition suppresses virus-induced expression of pro-inflammatory cytokines but enhances weight loss and mortality. In this proposal, we will test the hypothesis that increased IP activity during coronavirus infection drives immunopathology in an age-dependent manner. We will use a tractable animal model with an animal coronavirus, murine hepatitis virus type 1 (MHV-1), to define the role of the IP in coronavirus pathogenesis and identify effects of IP inhibition on virus-induced inflammation and disease during acute infection. In Aim 1, we will define age-based differences in IP response, inflammation, and disease induced by acute MHV-1 respiratory infection. In Aim 2, we will use pharmacologic inhibition of IP subunit activity to define effects of IP activity on key immune cells and determine the extent to which the IP contributes to virus-induced inflammation and disease. There is a clear and pressing need to development effective preventative and therapeutic measures for COVID-19. Modulation of an inducible host factor, such as the IP, that is predominantly active during an inflammatory state such as infection would be an appealing strategy if it could facilitate reduction of detrimental inflammatory responses with minimal impact on essential constitutively active host processes.

项目摘要严重的急性呼吸道综合征冠状病毒2（SARS-COV-2）是一种新型的人类冠状病毒引起2019年冠状病毒病（Covid-19）大流行。 COVID-19与严重，经常相关在很大一部分受影响的人中威胁生命的呼吸道疾病。严重的Covid-19是其特征是对SARS-COV-2感染产生的全身性炎症反应。这种响应有助于控制急性感染期间病毒复制表现。由于尚不完全理解的原因，有害的炎症反应是感染SARS-COV-2的儿童不太可能发育，而儿童比成年人更有可能无症状感染或轻度疾病。免疫蛋白酶体（IP），泛素 - 可诱导成分蛋白酶体系统，比本构蛋白酶体更有效地生成MHC I类表位 CD8 T细胞识别。 IP活动还对T细胞，B细胞，巨噬细胞和DC执行内在影响功能并通过包括IκB降解的机制来促进炎症反应随后的NF-κB介导的炎症途径的激活。没有研究解决人类或动物冠状病毒发病机理的IP。我们发布的初步数据表明 IP亚基活动在肺和其他器官中受到调节，随着年龄的增长而增加。 IP亚基在用鼠冠状病毒急性感染期间，小鼠的表达增加，IP抑制作用抑制病毒诱导的促炎细胞因子的表达，但增强了体重减轻和死亡率。在这个提案，我们将测试以下假设，即冠状病毒感染期间IP活动增加免疫病理学以年龄的方式。我们将使用动物的动物模型冠状病毒，鼠肝炎病毒1型（MHV-1），以定义IP在冠状病毒发病机理和确定抑制IP对病毒诱导的感染和急性感染期间疾病的影响。在AIM 1中，我们将定义急性MHV-1引起的IP反应，注射和疾病的基于年龄的差异呼吸道感染。在AIM 2中，我们将使用对IP亚基活性的药物抑制来定义IP的影响对关键免疫细胞的活性，并确定IP对病毒诱导的注射的贡献程度和疾病。明确而紧迫的需要开发有效的预防和治疗共同-19的措施。诱导宿主因子（例如IP）的调节主要是主动的在炎症状态（例如感染）期间，如果可以促进减少有害的炎症反应对基本活跃的宿主过程的影响最小。