伯氏疏螺旋体持续激活小胶质细胞“TLR1/2--FR-β-CD14正反馈环路”引起神经莱姆病及滇产天然产物雪胆甲素拮抗作用的机制研究

伯氏疏螺旋体（Bb)引起的神经莱姆病（LN)常进行性加重，危害很大。LN的发病机制未明。我们前期发现，Bb外膜蛋白bmpA能强力刺小胶质细胞产生促炎细胞因子，雪胆甲素可以拮抗bmpA的作用；离体猴脑在受到Bb及其外膜蛋白bmpA刺激后高表达叶酸受体β和CD14,伴随TLR信号通路激活。我们提出假说：Bb通过持续活化小胶质细胞TLR1/2-NF-κB-FRβ-CD14正反馈环路，导致神经系统的持续性炎症和进行性损伤，雪胆甲素可以抑制该环路的特定环节发挥抗炎作用。我们拟以人和动物小胶质细胞模型为研究焦点，以“TLR1/2-NF-κB-FRβ-CD14正反馈环路”为中心环节，用不同方法、从不同层次探索莱姆病螺旋体持续活化小胶质细胞、产生一系列炎症因子、导致中枢神经系统进行性损害、出现一系列LN症状和体征的潜在机制；研究雪胆甲素作用机制和靶点。为神经莱姆病发病机制和防治提供科学依据和防治新思路。

Lyme disease is an important insect-borne disease caused by Borrelia burgdorferi (Bb), in which Lyme neuroborreliosis (LN) is often progressively aggravated and very harmful. The pathogenesis of LN is clear. Our previous studies found that Bb outer membrane protein bmpA could strongly stimulate microglia to produce pro-inflammatory cytokines through TLR-NF-kappa B signaling pathway in vitro. The hemslecin A can antagonize the effect of bmpA. Brain explants highly expressed folate receptor beta and CD14 after being stimulated by Bb and its outer membrane protein bmpA, accompanied by activation of TLR signaling pathway, but the relationship among three phenomena is not clear. Based on our previous studies, we put forward the hypothesis ithat Bb can continuously activate and amplify "TLR1/2-NF-kappa B-FR beta-CD14 positive feedback loop" of microglia, leading to persistent inflammation and progressive damage of the nervous system. The hemslecin A can inhibit this loop to play an anti-inflammatory role. In order to testify the hypothesis, We intend to focus our research on human and animal microglia models, with TLR1/2-NF-κB-FR beta-CD14 positive feedback loop as the central link and logical chain, to explore the continuous activation mechanisms of microglia by Bb in different ways and levels to produce a series of inflammatory and toxic factors, and eventually to cause progressive damage to the central nervous system, and to produce a series of LN symptoms and signs. We will also study the mechanism and target by which the hemslecin A interfer with the positive feedback loop of microglia activation. The final goal is to provide scientific basis and new ideas for prevention and treatment for LN.