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 冠状病毒介导的人类呼吸道疾病，病死率高。疾病尤其严重， 老年人口。在上一个资助期，我们发现前列腺素的年龄依赖性增加， D2（PGD 2）和上游磷脂酶A2，PLA 2G 2D导致免疫应答差， 生存率下降。肺部处于慢性炎症状态，这是由于持续暴露于 环境抗原我们假设具有抗炎特性的PLA 2G 2D在细胞内表达上调， 为了对抗这种低度炎症，导致对无害抗原的反应延迟， 复制病毒如MERS冠状病毒和SARS冠状病毒。PGD 2信号传导的瞬时阻断或遗传缺失 PLA 2G 2D的表达大大增加了存活率。与此形成鲜明对比的是，“敲除”髓系细胞上的PGD 2受体DP 1， 细胞，将亚致死的SARS-CoV感染转化为致死感染，表明PGD 2/DP 1信号传导具有 在肺部感染中的作用。我们的中心假设是PGD 2和PLA 2G 2D沿着其他的 小脂质介质途径的成员在调节炎症状态中具有中心作用， 肺。具体来说，它们调节感染小鼠先天和随后T细胞反应的多个步骤。 SARS-CoV、MERS-CoV和其他可能的病毒性呼吸道病原体。这一假设将被探讨 具体目标如下：1.为了确定PLA 2G 2D上调的机制以及 PLA 2G 2D在12月龄小鼠中的疫苗应答中的作用CoV复制包括广泛的细胞膜 重新安排这些重排，氧化应激的诱导和 将研究PLA 2G 2D的上调。2.为了确定PGD 2-DP 1信号在免疫中的作用， 在12 m小鼠中对SARS-CoV的反应。PGD 2-DP 1信号转导的缺失导致rDC减少 活化和I型IFN（IFN-I）表达以及增加的炎性小体活化。我们的目标是确定 炎性小体活化的变化是否是PGD 2-DP 1信号传导缺失的主要致病作用， 如果还涉及其他因素。3.确定PGD 2和PLA 2G 2D是否导致不良结局 在感染MERS-CoV的小鼠中，另一种严重程度与年龄相关的感染。使用我们新的 开发的hDPP 4-KI小鼠和小鼠适应的MERS-CoV，我们将确定小鼠中的MERS-CoV是否 也会导致年龄依赖性疾病，以及类花生酸表达的变化是否会导致更多的 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.