L-丙氨酸促进抗菌肽表达提高宿主抗结核免疫机制研究

耐药结核已成为严峻临床问题，宿主靶向治疗（HDT）是最重要的解决方案，然而已知靶向宿主抗结核免疫的HDT药物却很有限。前期我们通过筛选及C57BL/6和SCID小鼠感染模型，发现L-丙氨酸可以通过天然免疫细胞保护宿主抵抗结核菌感染。在体外巨噬细胞感染模型中，L-丙氨酸可以促进抗菌肽的产生，甚至提高巨噬细胞对耐药结核菌的清除能力。以上前期数据提示结核病中L-丙氨酸是保护性代谢物，可能促进抗菌肽表达发挥保护作用。本项目拟进一步在体外模型中揭示L-丙氨酸促进抗菌肽表达的分子机制，并且利用L-丙氨酸作用靶点基因敲除小鼠明确L-丙氨酸是否通过促进抗菌肽表达，提高抗结核免疫。研究结果将首次提出L-丙氨酸是结核病重要保护性代谢物，为L-丙氨酸作为HDT药物开发提供明确机制，为临床治疗提供参考。同时，我们拓宽了小分子代谢物L-丙氨酸的免疫功能认识，为能量代谢产物在免疫调节中的研究提供范例。

As drug resistant tuberculosis has become a serious clinical problem, host targeted therapy (HDT) is one of the most important solution，however, little is known about HDT drugs targeting host anti-tuberculosis immunity. After screening and mice infection experiments, we found that L-alanine could protect the host against tuberculosis infection through innate immune cells. In macrophage in vitro infection model, L-alanine promotes the antimicrobial peptides exprssion, and even improves the clearance ability of macrophages to drug-resistant tuberculosis bacteria. These data suggest that L-alanine is a protective metabolite in tuberculosis, which may promote the expression of antimicrobial peptides and play a protective role. This project intends to reveal the molecular mechanism of L-alanine promoting the expression of antimicrobial peptides, and use L-alanine target gene knockout mice to determine whether L-alanine improves the anti-tuberculosis immunity by promoting the expression of antimicrobial peptides. This program will provide a clear mechanism for the development of L-alanine as an HDT drug and provide a reference for clinical treatment. At the same time, we broaden the understanding of the immune function of L-alanine, a small molecule metabolite, and give an example for the study of energy metabolites in immune regulation.