APLP2调控巨噬细胞对结核菌感染的免疫应答的机制研究

Identification and characterization of key immune regulators in the pathogenesis of tuberculosis is essential for the development of anti-TB approaches. APLP2 (Amyloid β (A4) precursor-like protein 2, APLP2) is involved in several physiological and pathological activities. However, the potential role of APLP2 in the process of Mtb infection remains unknown. Our previous work demonstrated that the expression of APLP2 in PBMC is lower in TB patients than healthy donors. We also observed that APLP2 significantly enhanced BCG-induced production of IL-6, IL-1β and IL-12. Besides, APLP2 could relieve the viable bacteria counts and lesion of pulmonary in Mtb infection. These findings suggest that APLP2 be an important regulator in Mtb infection through regulation of the immune response of macrophages. Here, we will characterize function and mechanism of APLP2 in the regulation of immune response of Mtb infected macrophages and the pathogenesis of TB by employing molecular and cell biology technology, mouse Mtb aerosol infection model and clinical samples analysis integratively. This study will provide novel molecular target and theoretical basis for the treatment of TB, especially multi-drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB).

结核菌感染致病过程中重要的免疫调控因子的鉴定和分析对于理解结核病的发病机制、开发新的诊疗手段十分重要。APLP2是淀粉样前体蛋白2，参与调控机体多种生理和病理活动，但在结核菌感染过程中的作用还未见报道。我们初步研究发现：（1）结核病患者外周血单个核细胞中APLP2的mRNA表达水平显著降低；（2）APLP2敲除的小鼠巨噬细胞感染结核菌后产生的IL-6、IL-1β、IL-12等细胞因子明显减少；（3）APLP2敲除的小鼠感染结核菌后肺组织的病变程度加重、肺内活菌数增多。以上结果提示APLP2可能是调节结核菌感染免疫应答的关键分子。为此，本项目将从分子水平、细胞水平、动物感染模型及临床样本分析等不同层次，研究APLP2调控结核菌感染免疫应答的作用机制，并明确其对结核菌感染过程的调节作用。研究结果可为结核病特别是耐药结核病的治疗提供新的分子靶标和理论基础。

作为最成功的病原体之一，2018年有160万人死于结核病。结核分枝杆菌(Mtb)已经发展出许多策略来逃避宿主抗菌介质，如一氧化氮(NO)。β淀粉样(A4)前体蛋白2,Aplp2,已经涉及到多个生理和病理活动;然而，其在结核病发病机制中的作用尚不清楚。在本研究中，我们发现在结核病患者和tb感染的巨噬细胞和小鼠中APLP2表达水平显著降低。此外，Aplp2的突变或敲低的巨噬细胞对Mtb的杀伤活性降低，且降低了一氧化氮合酶(iNOS)和各种细胞因子的表达,包括白介素-1β(IL-1β)。Aplp2突变小鼠与WT小鼠相比，更易感结核分枝杆菌，表现为组织病理学损害加重和肺部细菌负荷升高。Aplp2被 γ-secretase切割的产物AICD2会转移到细胞核,与p65互作,促进了NF-κB转录,从而诱导IL-1β和iNOS的表达。综上所述，Aplp2可能通过促进NO和IL-1β的表达介导的杀菌效应保护宿主不受分枝杆菌感染。因此，我们确定了一种结核菌的新的免疫逃避策略，可以作为结核病干预的靶点。