Role of eicosanoids in pathogenic human CoV infections

类二十烷酸在人类致病性冠状病毒感染中的作用

• 批准号: 9542722
• 负责人: Stanley Perlman
• 金额: $ 54.52万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9542722
• 关键词: Affect; Age; Age-Years; Aging; Alveolar Macrophages; Anti-inflammatory; Antigens; Case Fatality Rates; Cells; Cellular Membrane; Chronic; Coronavirus; Coronavirus Infections; Data; Dendritic Cells; Dendritic cell activation; Dependence; Depressed mood; Dinoprostone; Disease; Dopamine D2 Receptor; Eicosanoids; Elderly; Exposure to; Funding; Genetic; Goals; Human; ITGAX gene; Immune response; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Interferons; Knock-in Mouse; Knock-out; Lung; Lung diseases; Mediating; Middle East Respiratory Syndrome Coronavirus; Mus; Myeloid Cell Activation; Myeloid Cells; Outcome; Oxidative Stress Induction; Oxides; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phospholipase; Phospholipase A2; Phospholipids; Property; Prostaglandin D2; Prostaglandins; Respiratory Tract Infections; Role; Severe Acute Respiratory Syndrome; Severities; Severity of illness; Signal Transduction; T cell response; Up-Regulation; Vaccines; Viral; Virulent; Virus; age related; aged; aging population; base; cell motility; lipid mediator; lymph nodes; member; middle age; mortality; new therapeutic target; pathogen; receptor; respiratory; response; vaccine response

Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) are coronavirus-mediated human respiratory diseases with high case-fatality rates. Disease is especially severe in aged populations. In the previous funding period, we showed that age-dependent increases in prostaglandin D2 (PGD2) and an upstream phospholipase A2, PLA2G2D contributed to poor immune responses and decreased survival. The lung is in a state of chronic inflammation, resulting from continued exposure to environmental antigens. We postulated that PLA2G2D, which has anti-inflammatory properties, is upregulated to counter this low grade inflammation, resulting in delayed responses to innocuous antigens but also to rapidly replicating viruses like MERS-CoV and SARS-CoV. Transient blockade of PGD2 signaling or genetic absence of PLA2G2D greatly increased survival. In marked contrast, “knock-out” of DP1, the PGD2 receptor on myeloid cells, converted a sublethal SARS-CoV infection to a lethal one, indicating that PGD2/DP1 signaling has additonal roles in the infected lung. Our central hypothesis is that PGD2 and PLA2G2D along with other members of the small lipid mediator pathways have central roles in modulating the inflammatory state of the lung. In specific, they regulate multiple steps in the innate and subsequent T cell responses in mice infected with SARS-CoV, MERS-CoV and likely other viral respiratory pathogens. This hypothesis will be approached in the following specific aims: 1. To determine the mechanism of PLA2G2D upregulation and the role of PLA2G2D in vaccine responses in 12m old mice. CoV replication includes extensive cellular membrane rearrangements. The role between these rearrangements, the induction of oxidative stress and the upregulation of PLA2G2D will be investigated. 2. To determine the role of PGD2-DP1 signaling in the immune response to SARS-CoV in 12 m mice. The absence of PGD2-DP1 signaling results in diminished rDC activation and type I IFN (IFN-I) expression and increased inflammasome activation. Our goal is to determine whether changes in inflammasome activation are the major pathogenic effect of absent PGD2-DP1 signaling or if other factors are also involved. 3. To determine whether PGD2 and PLA2G2D contribute to poorer outcomes in mice infected with MERS-CoV, another infection in which severity is age-dependent. Using our newly developed hDPP4-KI mice and mouse-adapted MERS-CoV, we will determine whether MERS-CoV in mice also causes an age-dependent disease and whether changes in eicosanoid expression contribute to more severe disease.

中东呼吸综合症（MERS）和严重的急性呼吸道综合征（SARS）为 冠状病毒介导的人类呼吸道疾病具有较高的病例竞争率。疾病特别严重 老年人。在上一个资金期间，我们表明前列腺素依赖年龄的增加 D2（PGD2）和上游磷脂酶A2，PLA2G2D导致免疫复杂不良和 生存降低。肺部处于慢性炎症状态，持续暴露于 环境抗原。我们假设具有抗炎特性的PLA2G2D已更新 应对这种低年级炎症，导致对无害抗原的反应延迟 复制MERS-COV和SARS-COV等病毒。 PGD​​2信号传导或遗传吸收的瞬态阻断 PLA2G2D的生存率大大增加了。与之形成鲜明对比的是，DP1的“敲除”，髓样的PGD2受体 细胞将余生的SARS-COV感染转化为致命的感染，表明PGD2/DP1信号传导具有 在感染的肺中作用。我们的中心假设是PGD2和PLA2G2D以及其他 小脂质介质途径的成员在调节炎症状态中具有核心作用 肺。特别是，它们在感染的小鼠中的先天和随后的T细胞反应中调节多个步骤 带有SARS-COV，MERS-COV以及可能的其他病毒呼吸道病原体。该假设将被解决 在以下具体目的中：1。确定PLA2G2D上调的机理和 12m旧小鼠的疫苗反应中的PLA2G2D。 COV复制包括广泛的细胞膜 重排。这些重排的作用，氧化应激的诱导和 将研究PLA2G2D的上调。 2。确定PGD2-DP1信号在免疫中的作用 12 m小鼠中对SARS-COV的反应。没有PGD2-DP1信号传导导致RDC减少 激活和I型IFN（IFN-I）表达并增加炎症体激活。我们的目标是确定 炎性体激活的变化是没有PGD2-DP1信号传导还是 如果还涉及其他因素。 3。确定PGD2和PLA2G2D是否有助于较差的结果 在感染MERS-COV的小鼠中，这是严重程度依赖年龄的另一种感染。使用我们的新 开发了HDPP4-KI小鼠和小鼠适应的MERS-COV，我们将确定小鼠中的MERS-COV是否是 还会导致年龄依赖性疾病，以及类os酸表达的变化是否有助于更多 严重疾病。