固有免疫细胞及IL-33/ST2-IL-13应答轴在RSV诱发急性哮喘中的作用研究

Infection with respiratory syncytial virus （RSV）causes acute asthma. Conventional asthma therapies, such as corticosteroids, which effectively limit the function of eosinophils and Th2 cells, have not been as effective as hoped in many clinical trials of RSV-induced asthma. Such findings suggest that additional pathologic mechanism and pathway, which distinct from that involved in allergic asthma, might underlie the development of non-allergic forms of asthma triggered by viral infection. In the previous study, we found that infection of BALB/c mice with respiratory syncytial virus increased production of IL-33 and IL-13 in the lungs of tested mice. RSV infection resulted in rapid development of airway hyper-reactivity (AHR) that peaked on day 5 and retuned to normal level on day 12 of infection. The occurrence of a local virus-specific CTL response in the lung parenchyma cells of BALB/c mice was evident, peaking at day 10 after intranasal virus infection. No statistical difference in antibody titers of total IgE as well as RSV-specific IgE between RSV-infected mice and corresponding control mice was detected. These results suggest that comparing with adaptive cells and adaptive immunity, local innate cells as well as IL-33-IL-13 axis could contribute to the development of RSV-induced acute asthma. .In the present study, we use established experimental mouse model in which we infected mice with respiratory syncytial virus and examine the development of acute AHR and airway inflammation. We are interested in: ① whether airway inflammation and airway hyper-reactivity induced by RSV infection depend on IL-33, its receptor (ST2) and local innate immune cells; ②whether infection with RSV activates the IL-33/ST2-IL-13 axis, and ③ whether the axis is required for the development of RSV-induced acute asthma. This study may lead to improved therapies for non-allergic forms of asthma triggered by viral infection.

RSV感染诱发急性哮喘。而常规的哮喘治疗药物对其治疗效果不佳，提示在RSV急性哮喘中，存在着不同于过敏性哮喘的致病机制或途径。我们前期研究发现，RSV感染诱发BALB/c鼠气道高反应性，其峰值出现在感染后第5天，感染后第12天降至正常；但病毒特异性细胞应答在感染后第5天出现，第10天达高峰；血清总IgE及RSV特异性IgE水平未发生明显变化，提示与适应性应答相比，固有应答在RSV急性哮喘中更重要。RSV哮喘鼠肺细胞高水平分泌IL-33和IL-13，推测IL-33-IL-13应答轴参与RSV哮喘。本项目旨在进一步证实RSV急性哮喘的发生依赖固有免疫细胞，明确介导RSV哮喘的固有免疫细胞类型及其活化和效应机制，同时揭示IL-33/ST2-IL-13应答轴在病毒感染、固有免疫细胞和急性哮喘之间信息交流中的作用，为开发研制哮喘，尤其是病毒感染诱发的非过敏性哮喘治疗新药及临床治疗提供新思路和新靶标。

在病毒感染诱发的非过敏性哮喘中，呼吸道合胞病毒（respiratory syncytial virus, RSV）感染诱发的急性哮喘最为常见。常规的过敏性哮喘治疗药物，如可有效抑制嗜酸粒细胞和Th2细胞功能的皮质甾类药物对其治疗效果不佳，提示在RSV感染诱发的急性哮喘发生过程中，存在着不同于过敏性哮喘的某些致病机制或途径。本研究项目着眼于固有免疫细胞，尤其是肺泡巨噬细胞、天然辅助细胞，探讨其在RSV急性哮喘发生发展过程中活化及效应相关分子机制，阐明IL-33/ST2-IL-13应答轴在病毒感染和固有细胞之间信息交流中的作用，为开发研制支气管哮喘，尤其是病毒感染诱发的非过敏性哮喘的治疗新药以及临床治疗提供了新思路和新靶标。.研究发现RSV感染诱发BALB/c鼠气道炎症和气道高反应性，同时导致实验鼠肺组织局部IL-33水平明显升高。包括肺泡巨噬细胞、肺树突状细胞在内的固有免疫细胞是感染早期IL-33的主要来源细胞。这些固有免疫细胞利用TLR3、TLR7受体识别病毒抗原，活化JNK、ERK、P38等信号转导通路，进而合成并分泌IL-33。IL-33作用于表达其受体ST2的免疫细胞，尤其是天然辅助细胞，促进其增殖活化，诱导其分泌Th2型细胞因子，介导气道炎症和嗜酸细胞肺浸润。MyD88、IRAK4、P38信号通路可能在IL-33活化天然辅助细胞中发挥关键作用。. 本项目自2013年1月1日开始至2016年12月31日结束，共发表SCI学术论文4篇，中文核心期刊论文6篇，会议论文1篇，待发表SCI论文3篇。培养博硕士研究生10人，按预定计划圆满完成课题预定目标。