Immunoproteasome-Mediated Inflammation in Coronavirus Respiratory Infection

项目总结 严重急性呼吸综合征冠状病毒2(SARS-CoV-2)是一种新型的人类冠状病毒，具有 导致2019年冠状病毒病(新冠肺炎)大流行。新冠肺炎与严重的、频繁的 在相当大比例的受影响人群中，有危及生命的呼吸道疾病。严重的新冠肺炎是 以对SARS-CoV-2感染产生旺盛的全身炎症反应为特征。这一反应有助于 在急性感染期间控制病毒复制，但它也推动病毒诱导的病理和疾病 表现形式。由于尚不完全清楚的原因，这种有害的炎症反应是 感染SARS-CoV-2的儿童患上SARS-CoV-2的可能性较小，而儿童比成年人更有可能患上 无症状感染或轻微疾病。免疫蛋白酶体(IP)是泛素的一种可诱导成分-- 蛋白酶体系统，在产生MHC I类表位方面比构成蛋白酶体更有效 CD8T细胞的识别。IP活性也对T细胞、B细胞、巨噬细胞和DC产生内在影响 通过包括I-κB和I-DNA降解在内的机制发挥作用并促进炎症反应 随后激活核因子-κB介导的炎症通路。还没有研究涉及到 IP对人或动物冠状病毒的致病作用。我们公布的和初步的数据表明 IP亚单位的活性在肺和其他器官中受到发育调节，随着年龄的增长而增加。IP子单元 小鼠在急性感染小鼠冠状病毒期间表达增加，IP抑制抑制 病毒诱导的促炎细胞因子的表达，但会增加体重减轻和死亡率。在这 提议，我们将检验假设，在冠状病毒感染期间IP活性增加驱动 以年龄相关的方式进行免疫病理学研究。我们将使用一个易驯服的动物模型和一只动物 冠状病毒，小鼠肝炎病毒1型(MHV-1)，以确定IP在冠状病毒发病机制中的作用 确定IP抑制在急性感染期间对病毒引起的炎症和疾病的影响。在目标1中，我们 将确定急性MHV-1引起的IP反应、炎症和疾病的年龄差异 呼吸道感染。在目标2中，我们将使用对IP亚单位活性的药物抑制来定义IP的影响 关键免疫细胞的活性，并确定IP在病毒诱导的炎症中的作用程度 和疾病。开发有效的预防和治疗方法显然是迫切需要的。 《新冠肺炎》实施办法。对主要活跃的可诱导主机因素的调制，例如IP 在炎症状态期间，如感染，如果它能促进减少 有害的炎症反应，对基本的、构成上活跃的宿主过程的影响最小。

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.