青环海蛇免疫调节肽Hc-CATH抗耐药菌感染的分子机理研究

免疫疗法治疗耐药菌感染潜力巨大。我们从海蛇体内发现的免疫调节肽Hc-CATH作用机制新颖，通过竞争性结合巨噬细胞膜表面TLR4/MD2受体抑制LPS诱导的炎症。此外，该多肽能显著降低耐甲氧西林金葡菌感染小鼠的死亡率和体内细菌负荷量，诱导巨噬细胞趋化因子表达并提高其吞噬杀菌能力，诱导中性粒细胞外陷阱（NETs）形成。据此我们推测：Hc-CATH通过诱导吞噬细胞趋化并提高细胞吞噬杀菌能力的双重机制杀灭耐药菌。为证实该推测，本课题将首先从细胞和动物模型水平研究Hc-CATH体内外诱导巨噬细胞和中性粒细胞趋化及趋化因子表达的功能及其机理；进一步研究其对细胞吞噬、呼吸爆发和细胞内抗菌多肽和抗菌蛋白表达的影响；最后研究其提高细胞吞噬和杀菌能力的机理，特别是促进NETs形成的机理。通过本课题，期望为抗耐药菌感染免疫调节肽药物的设计提供分子模板和理论支持。

Immunotherapy is a promising treatment for drug-resistant bacterial infections. Hc-CATH, an immunomodulatory peptide identified from sea snake, possesses novel immunomodulatory mechanism. It inhibited the LPS-induced inflammation by competitive binding to the TLR4/MD2 receptor on the membrane surface of macrophages. Besides, it significantly reduced the mortality and bacterial load in MRSA-infected peritonitis mice. And it induced the production of chemokines in macrophage, enhanced the bactericidal ability of macrophage, and induced the formation of neutrophil NETs. Accordingly, we speculated that Hc-CATH kills the drug-resistant bacteria through inducing the chemotaxis of phagocytic cells and enhancing their phagocytosis. In order to confirm the hypothesis, in the present project we will firstly study the function and mechanism of Hc-CATH in inducing macrophage and neutrophil chemotaxis and chemokine expression in cells and mice model. And then, the functions of Hc-CATH in inducing phagocytosis, respiratory burst, and antimicrobial peptide and protein expression of macrophages and neutrophils will be studied. Finally, the mechanisms of Hc-CATH in enhancing the phagocytosis and bactericidal action, especially the mechanism of inducing NETs formation will be studied. Through the present project, we expect to provide templates and theoretical supports for the design of immunomodulatory peptide drugs against drug-resistant bacterial infections.