腺苷合成酶促进猪链球菌脑膜炎形成的细胞和分子机制研究

Streptococcus suis (S. suis) is an important emerging zoonotic agent that causes acute bacterial meningitis in humans with sudden onset, rapid disease progression and a high rate of mortality and morbidity. The pathogenesis of S. suis is still unclear. S. suis adenosine synthase (Ssads) is an important virulent factor which contributes to escape human innate immunity and improve bacterial survival in blood by synthesis of adenosine. Since adenosine could increase the permeability of blood–brain barrier (BBB) by binding adenosine receptors, we suppose that Ssads might play important roles on the development of S. suis meningitis. In this proposal, using a human BBB model and a murine model of S. suis meningitis, we plan to investigate whether Ssads is involved in the traversal of S. suis across the BBB and the permeability changes of the BBB during S. suis infection. Next, we plan to study the functions and mechanisms of adenosine receptors on the development of S. suis meningitis. In addition, we plan to investigate whether the homologous proteins of Ssads expressed in other bacteria have similar functions. We hope this study might contribute to learn the mechanism of S. suis meningitis, learn the functions and mechanism of bacterial adenosine synthases on the development of meningitis and introduce some scientific data for the prevention and cure of S. suis infection.

猪链球菌是重要的新发病原体，人感染猪链球菌可引起急性脑膜炎等临床症状，具有起病急、病程短，病死率和病残率高的特点，但其致病机制尚不完全清楚。腺苷合成酶Ssads是猪链球菌重要的毒力因子，其可通过合成腺苷帮助细菌逃避宿主的天然免疫，提高细菌血中存活能力。由于腺苷与其受体结合能提高血脑屏障通透性，我们推测Ssads在猪链球菌脑膜炎形成过程中可能具有重要功能。因此，本项目拟利用人血脑屏障细胞模型和小鼠脑膜炎模型，评价Ssads对猪链球菌穿血脑屏障能力和血脑屏障通透性的影响，研究在Ssads介导的猪链球菌脑膜炎形成过程中，腺苷受体的功能及作用机制。此外，本项目还拟评价Ssads在其它细菌中的同源蛋白是否有类似功能。我们相信本项目的研究有助于加深对猪链球菌脑膜炎致病机制的认识，有助于了解细菌腺苷合成酶在致脑膜炎中功能和机制，为人感染猪链球菌病的防治提供科学依据。

猪链球菌是重要的新发病原体，人感染猪链球菌可引起急性脑膜炎等临床症状，具有起病急、病程短，病死率和病残率高的特点，但其致病机制尚不完全清楚。腺苷合成酶Ssads是猪链球菌重要的毒力因子，其可通过合成腺苷帮助细菌逃避宿主的天然免疫，提高细菌血中存活 能力。由于腺苷与其受体结合能提高血脑屏障通透性，我们在本项目中探讨Ssads在猪链球菌穿过血脑屏障过程中的具体功能。我们发现，猪链球菌Ssads 诱导的腺苷生成有助于这种病原菌进入小鼠大脑。在人类微脑血管内皮体外血脑屏障模型上多种抑制剂和激动剂的筛查实验共同证明，A1腺苷受体激活信号以及引发的细胞骨架重构能够促进猪链球菌穿过血脑屏障。此外，我们的研究数据表明，来自其他细菌的 Ssads 同源腺苷合成酶也促进了它们穿过血脑屏障，这提示利用A1腺苷受体信号穿过宿主血脑屏障可能是这类细菌的通用毒力机制。