Axl负向调控TLR-MAPKs信号通路在重症肺结核发病中的作用及机制研究

重症肺结核因其高致残率、高死亡率、强传染性，严重威胁患者生命健康及社会卫生安全。前期对临床样本高通量芯片筛选，发现血浆sAxl含量可作为诊断重症肺结核的血液学标志物。Axl属于受体酪氨酸激酶，是一个重要的跨膜糖蛋白。随后研究显示：⑴结核菌感染促进了Axl胞外段剪切，这一过程与肺结核病情严重程度呈显著正相关。Axl胞外段剪切对Axl功能起到负向调控作用。⑵结核菌感染巨噬细胞模型显示：Axl基因敲除后，MAPKs信号通路显著激活；⑶结核菌感染小鼠模型显示：抑制Axl活性后，感染小鼠肺部病理损伤明显加重、肺组织荷菌量明显增加。因此我们推测Axl负向调控MAPKs信号通路在结核菌感染、尤其重症肺结核发病过程中具有重要作用。为此本项目将从分子、细胞、动物感染模型等不同层次，探索Axl负调控TLR-MAPKs信号通路在重症肺结核发病中的作用及机制，为重症肺结核的诊治提供新思路、新靶标及新干预手段。

Identification and characterization of key immune regulators in the pathogenesis of tuberculosis is essential for the development of anti-TB approaches. Axl belongs to receptor tyrosine kinases, and is involved in several physiological and pathological activities. However, the potential role of Axl in the process of Mtb infection remains unknown. Membrane-bound Axl can be shed from the cell membrance and released into circulation as a soluble form, sAxl. Our previous work demonstrated the plasma levels of sAxl was a biomarker for severe PTB. Sequent studies showed that (1) Mtb infection regulated the cleavage of Axl extracellular segment, which was closely related to the severity of clinical diseases; (2) Cellular level researches showed Axl negatively regulated MAPKs signaling pathway in Mtb infection; (3) Animal level studies showed that inhibition of Axl activity could aggravate the lung pathological injury and increase the amount of bacteria in the lung tissue. These results suggest Axl may play an important role in the pathogenesis of severe pulmonary tuberculosis by negatively regulating TLR-MAPKs signaling pathway. Therefore, this project will further explore the role and mechanism of Axl negative regulation of TLR-MAPKs signaling pathway in the formation of severe pulmonary tuberculosis from molecular, cellular and animal infection models, so as to provide new molecular targets and interventions for the diagnosis and treatment of severe pulmonary tuberculosis.