MLL1 drives collaborative leukocyte-endothelial cell signaling and thrombosis after coronavirus infection

项目摘要/摘要 严重感染新冠肺炎(严重急性呼吸综合征冠状病毒-2；SARS-CoV-2) 导致许多生理紊乱，包括急性呼吸窘迫综合征(ARDS)和肾脏 失败了。SARS-CoV-2感染继发的破坏性后遗症预示着显著的发病率和死亡率 发生的部分原因是宿主炎症反应失调，从而导致组织损伤。COVID的标志- 19病理生理学表现为严重的内皮炎、强烈的炎性细胞浸润和微血栓形成9倍以上 比致命性流感更常见。内皮反应性和损伤被认为发生在对 炎性细胞因子的刺激和累积导致内皮屏障功能的丧失 内皮细胞黏附分子(CAM)表达失调导致水肿和炎症 SARS-CoV-2感染后，在许多血管床上可见细胞穿透间质组织。 此外，内皮细胞的激活进一步使促炎因子的产生永久化，并且 观察到内皮细胞凸轮的显著释放，并推测其作为一种化学吸引剂作用于 免疫细胞如MO/MφS。总的来说，内皮细胞可能在血管内皮细胞的调节中起着不可或缺的作用 冠状病毒感染后的伤害性后遗症。越来越多的证据表明，表观遗传学 通过活性调节(对DNA及其相关蛋白质的共价修饰[例如，组蛋白]) MO/Mφ中染色质修饰酶(CME)是导致细胞表型改变的主要原因 冠状病毒感染。我们已经鉴定出一种组蛋白赖氨酸甲基转移酶，混合细胞性白血病1(MLL1)， 作为冠状病毒感染后细胞黏附分子诱导的介质。我们假设MLL1 内皮细胞的表达驱动内皮细胞的激活和损伤，并与先天免疫协同作用 冠状病毒感染后驱动组织损伤的细胞。这一假设将通过两个具体目标进行调查- 1)检测冠状病毒诱导的MLL1如何改变CAM基因表达和内皮细胞表型。 2)研究MLL1阻断如何改变血栓形成和内皮通透性 冠状病毒在体外和体内的暴露。

Project Summary/Abstract Severe infection with the COVID-19 (severe acute respiratory syndrome coronavirus-2; SARS-CoV-2) results in numerous physiologic derangements including acute respiratory distress syndrome (ARDS) and renal failure. Injurious sequelae secondary to SARS-CoV-2 infection portend a significant morbidity and mortality and occur in part due to dysregulated host inflammatory response with resulting tissue injury. The hallmark of COVID- 19 pathophysiology is severe endotheliitis, intense inflammatory cell infiltrate and microthrombosis 9x more common than lethal influenza. Endothelial responsiveness and injury are thought to occur in response to inflammatory cytokine stimulation and cumulatively result in the loss of endothelial barrier function through dysregulation of endothelial cellular adhesion molecule (CAM) expression resulting in edema and inflammatory cell penetration of interstitial tissues which is seen in numerous vascular beds after SARS-CoV-2 infection. Additionally, endothelial cell activation further perpetuates the production of proinflammatory factors, and a prominent release of endothelial CAMs is observed and is postulated to function as a chemoattractant for immune cells such as MO/Mφs. Collectively, endothelial cells may play an integral role in the mediation of injurious sequelae in a post-coronavirus infected state. Accumulating evidence suggests that epigenetic regulation (covalent modifications to DNA and its associated proteins [e.g., histones]) through the activity of chromatin modifying enzymes (CMEs) in MO/Mφs is responsible for cellular phenotypic changes after coronavirus infection. We have identified a histone lysine methyltransferase, mixed lineage leukemia 1 (MLL1), as a mediator of cellular adhesion molecule induction following coronavirus infection. We hypothesize that MLL1 expression in endothelial cells drives endothelial activation and injury and works in concert with innate immune cells to drive tissue injury after coronavirus infection. This hypothesis will be investigated by two specific aims – 1) To examine how coronavirus-induced MLL1 alters CAM gene expression and endothelial phenotype. 2) To examine how MLL1 blockade alters thrombosis and endothelial permeability in response to coronavirus exposure in vitro and in vivo.