Role of eicosanoids in pathogenic human CoV infections

中东呼吸综合征(MERS)和严重急性呼吸综合征(SARS)是 冠状病毒介导的高病死率的人类呼吸道疾病。疾病在中国尤为严重 老龄化人口。在之前的资助期间，我们表明前列腺素水平随年龄的增加而增加 D2(PGD2)和上游磷脂酶A2，PLA2G2D导致免疫反应不良和 存活率下降。肺部处于慢性炎症状态，这是由于持续暴露于 环境抗原。我们推测，具有抗炎作用的PLA2G2D表达上调 为了对抗这种低级别的炎症，导致对无害抗原的延迟反应，但也迅速 复制病毒，如MERS冠状病毒和SARS冠状病毒。PGD2信号一过性阻断或遗传缺失 PLA2G2D的表达显著提高了存活率。与之形成鲜明对比的是，髓系上的PGD2受体DP1的“敲除” 细胞，将亚致死的SARS-CoV感染转化为致命的，表明PGD2/DP1信号转导 在感染的肺中起着额外的作用。我们的中心假设是PGD2和PLA2G2D以及其他 小分子脂质介体通路成员在调节血管炎症状态中起核心作用。 阿龙。具体地说，它们调节感染小鼠的先天和随后的T细胞反应的多个步骤 与SARS冠状病毒、MERS冠状病毒和可能的其他病毒性呼吸道病原体有关。这一假设将会得到证实。 具体目的如下：1.确定PLA2G2D上调的机制及其作用 PLA2G2D在1200万只老年小鼠的疫苗应答中的作用冠状病毒复制包括广泛的细胞膜 重新安排。这些重排、氧化应激诱导和 将研究PLA2G2D的上调。2.确定PGD2-DP1信号在免疫中的作用 1200万只小鼠对SARS冠状病毒的应答。缺少PGD2-DP1信号会导致RDC减少 激活和I型干扰素(IFN-I)的表达，并增加炎症体的激活。我们的目标是确定 炎性小体激活的改变是PGD2-DP1信号缺失的主要致病作用还是 如果还涉及其他因素的话。3.确定PGD2和PLA2G2D是否会导致较差的结果 在感染MERS冠状病毒的小鼠中，另一种严重程度与年龄有关的感染。使用我们的新功能 建立hDPP4-Ki小鼠和小鼠适应的MERS冠状病毒，我们将确定MERS冠状病毒在小鼠体内 也会导致年龄依赖性疾病，以及二十烷类化合物表达的变化是否有助于 严重的疾病。

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.