Ⅱ型肺泡上皮细胞中抗菌肽hBD-1活化的自噬调节机制及其抗结核免疫效应

AEC-Ⅱ细胞兼具肺泡上皮修复与免疫调节活性，是肺泡上皮屏障抵御MTB感染的重要组成。抗菌肽hBD-1在上皮细胞中持续表达，构成宿主防御上皮感染的第一道防线，但其调节AEC-Ⅱ抗MTB感染的效应与机制未知。课题组发现结核患者及BCG感染的AEC-Ⅱ中，hBD-1表达上调，显著抑制胞内BCG存活，其活化与自噬相关，并参与自噬杀菌。据此提出假说：自噬是hBD-1胞内酶切活化的机制，并且是其氧化还原活性调节途径的前提；活化的hBD-1参与自噬杀菌，促进AEC-Ⅱ抗MTB感染活性。项目拟进一步检测MTB感染AEC-Ⅱ中自噬对hBD-1活化与杀菌效应的调节，探讨自噬调节其活化的机制；检测hBD-1氧化还原状态及与杀菌效应的关联，探讨自噬对该途径的调节。项目将揭示MTB感染AEC-Ⅱ中hBD-1的活化机制，为通过自噬调节其功能、增强AEC-Ⅱ抗MTB感染活性的抗结核免疫疗法提供依据。

On an account of the activities of both alveolar epithelial repairment and immunoregulation, the alveolar type II epithelial cell (AEC-II) is one important component of the alveolar epithelial barrier against MTB infection. The antimicrobial peptide hBD-1 is continuously expressed in epithelial cells and constitutes the host’s first line of defense against epithelial infection, but its effect and mechanism of regulating AEC-II’s resistance to MTB infection are still unknown. The research team found that hBD-1 expression was up-regulated in tuberculosis patients and AEC-II infected by BCG, which significantly inhibited BCG survival in AEC-II. Activation of hBD-1 was related to autophagy and hBD-1 was involved in autophagy sterilization. Accordingly, we propose the hypothesis that, autophagy is the intracellular enzymatic digestion mechanism of hBD-1 activation, and is also the prerequisite for the redox activity regulation pathway of hBD-1. Activated hBD-1 participates in autophagy sterilization and promotes the anti-MTB infection activity of AEC-II. The project intends to further verify the regulation of hBD-1 activation and bactericidal effects by autophagy in MTB-infected AEC-II, explore the regulatory mechanism of hBD-1 activation by autophagy; subsequently, detect the redox status of hBD-1 in MTB-infected AEC-II and its association with the bactericidal effect, and explore the effect of autophagy on regulation of this pathway. The project will reveal the activation mechanism of hBD-1 in MTB-infected AEC-II, and provide the basis for the novel anti-tuberculosis immunotherapy that enhances the anti-MTB infection activity of AEC-II through regulating hBD-1 function by autophagy.