新型警报素IL-33参与汉滩病毒感染内皮细胞诱导促炎因子产生的分子机制

Hantaan virus (HTNV) is a major agent causing hemorrhagic fever with renal syndrome (HFRS) with a high-mortality-rate. Hallmarks of HFRS include microvascular hemorrhage and renal failure. The production of excessive pro-inflammatory cytokines is a key factor causing the disease pathological injury. Interleukin-33 (IL-33), defined as a novel alarmin, is a new member of the IL-1 cytokine family. Previously we found that the increased level of IL-33 in HFRS patients’ plasma was closely correlated with the severity of the disease. In vitro, IL-33 treatment and HTNV infection induced excessive pro-inflammatory cytokines. However, during HTNV infection, the mechanisms for the production of pro-inflammatory cytokine remain unclear. This project aims to reveal the cross-talk between the IL-33/ST2 signaling pathway and the HTNV infection pathway in endothelial cells. Furthermore, it will elucidate the molecular mechanisms of the production of pro-inflammatory cytokines during both HTNV infection and IL-33 treatment in endothelial cells. Especially, the role of the tumor necrosis factor receptor associated factor 6 (TRAF6) and de-ubiquitination enzyme A20 playing in the regulation of NF-κB pathway and their downstream cytokines’ production during HTNV infection and IL-33 stimulation will be explored. Our study may help to better understand the mechanisms underlying the production of pro-inflammatory cytokines during HTNV infection and may provide a novel therapeutic target of HTNV infection.

汉滩病毒(HTNV)感染引起的肾综合征出血热(HFRS)病死率高。微血管损伤、出血和肾功能损害等是本病主要的病理特征。大量炎症因子的产生是引起本病病理损伤的关键因素。IL-33属于IL-1家族成员，是一种新型警报素。我们前期研究发现，HFRS患者血浆中IL-33水平显著升高，与病情密切相关。体外实验发现IL-33刺激协同HTNV感染内皮细胞产生多种炎症因子。目前有关HTNV感染引起促炎因子产生的分子机制尚未明晰。本课题拟在证实IL-33联合HTNV感染内皮细胞介导信号通路间存在Cross-talk的基础上，进一步阐明IL-33联合HTNV感染导致内皮细胞产生促炎因子的分子机制，尤其是肿瘤坏死因子受体相关因子6 (TRAF6）及去泛素化酶A20的活化程度对下游NF-κB通路的调控及炎症因子产生的作用，加深对HTNV感染后促炎因子产生机制的认识，并为HFRS临床治疗提供新的理论和实验依据。

肾综合征出血热（ hemorrhagic fever with renal syndrome, HFRS） 由汉滩病毒（ Hantaan virus, HTNV）感染所致，病死率高。微血管损伤、出血和肾功能损害等是本病主要的病理特征。大量炎症因子的产生是引起本病病理损伤的主要因素。IL-33属于IL-1家族成员，是一种新型警报素。首先，我们发现HFRS患者血浆中IL-33水平显著升高，与病情密切相关。随后，体外实验发现IL-33刺激协同HTNV感染内皮细胞产生多种炎症因子。为了进一步研究IL-33在 HFRS 中发挥的免疫调节作用及HTNV感染引起促炎因子产生的分子机制。本课题通过对HFRS血浆中 IL-33 及 sST2 的含量检测及其与患者病情相关性分析，体外 HTNV 感染内皮细胞模型检测 IL-33/ST2 对内皮细胞发生炎症反应的调控及IL-33/ST2 与 HTNV 感染协同调控内皮细胞炎症反应的分子机制进行探索。我们发现IL-33及其受体sST2在HFRS血浆中均高表达且与患者病情严重程度均呈正相关，二者含量之间也呈正相关。体外 HTNV 感染内皮细胞模型中发现，IL-33可通过ST2介导的途径促进 HTNV 感染的内皮细胞产生大量的促炎细胞因子，促进内皮细胞发生炎症反应。而sST2则可抑制内皮细胞炎症反应的发生。 而且,IL-33和HTNV通过共同活化NF-NF-κB 途径达到协同促进炎症反应的作用。该研究提示 IL-33 可能是HTNV感染导致“细胞因子风暴”的诱发因子，而该炎症反应的过程可被 sST2 抑制。 IL-33/ST2 共同调控 HTNV 感染后的免疫应答。本研究加深了人们对HTNV感染后促炎因子产生机制的认识，并为HFRS临床治疗提供新的理论和实验依据。