抗生素应用已取得巨大成果，但细菌感染引起的败血症和脑膜炎(BSM)仍是新生儿死亡主要原因，且大肠埃希菌(E.coli)是BSM最常见病菌。研究发现，宿主α7乙酰胆碱受体(α7R)在E.coli穿越血脑屏障(BBB)引发BSM过程起关键作用，但机制不明。通过体内外BBB模型、α7R敲除动物实验和RNA测序，我们发现美金刚(MEM)可阻断由脑膜炎E.coli E44感染引起的α7R活化。通过化学阻断或基因敲除(KO)屏蔽α7R功能均可显著降低BSM造成的脑损伤，其机制可能是上调宿主蛋白SA9和A20提高中性粒细胞胞外杀菌网络(NET)活性。本项目将从细胞、离体(脐血)及整体(α7R/SA9敲除小鼠模型)层面，采用实时动态成像、单细胞分析法(SCP)、RABT和双转录组/蛋白组等技术，研究MEM以α7R为靶点的NET抗菌机理，结合MEM药物学实验及药物间联合应用，寻找有效防治BSM策略。

Despite the availability of antibiotics over the last several decades, an unmet need still exists for new effective therapeutic approaches to treat neonatal infections. Most of these deaths are caused by bacterial sepsis and meningitis (BSM), which is characteristic of high mortality and adverse prognosis. The most common gram negative bacterial pathogens causing BSM is E. coli. We have demonstrated that nAchR (α7R) played a detrimental role in the genesis of bacteremia and pathogen penetration across the blood-brain barrier (BBB), but the pathogenic mechanism of BSM is still unknown. Using the α7R knockout mice, we found that α7R is critical for the pathogenesis of BSM. The findings support the notion that α7R could serve as a unique drug target for therapeutic interventions against BSM. Using in vitro/in vivo models of BBB and RNA-seq, our drug repositioning studies have shown that MEM could very efficiently block BSM caused by E. coli E44 and enhance phagocytosis and neutrophil extracellular trap (NET)-mediated bacterial activity in a manner dependent on SA9 protein and A20 protein. Therefore, we hypothesize that MEM is a novel α7R target drug for treatment of BSM through enhancing the activity of NETS which will be examined by cell culture systems and KO animal models.