Mga-like介导的环境信号调控CPS在肺炎链球菌侵袭性致病中的作用机制

Streptococcus pneumoniae is a significant clinical condition pathogen causing both mucosal, pneumonia, and systemic diseases, but also the first community-acquired pneumonia pathogen. The capsular is an important virulence factor of Streptococcus pneumoniae, and the regulation of the capsular production by living environment signal is an important way of bacterial survival environment, but little is known about the transcription regulators of cps in this signal way. In the present study, we isolated and identified the response regulator, Mga-like, as a transcriptional regulator of cps locus by DNA -pulldown, MALDI-TOF-MS and EMSA, and proved to have negative-regulated CPS and positive-regulated teichoic acid. Mga-like, which can sense the glucose concentration to regulate the CPS production, is highly homologous to environmental signal-regulated transcription factor Mga in Streptococcus pyogenes. In this study, we plan to explore the environment signals of Mga-like mediated capsular production regulation and clarify the the mechanism of the infection of Streptococcus pneumoniae through Mga-like mediated capsular regulation. This study is of great significance to understand the mechanism of bacterial adaptation to different environment in vivo, and may provide a new target for the prevention and treatment of pneumococcal diseases.

肺炎链球菌是一种临床常见的条件致病菌，也是社区获得性肺炎的首位细菌病原菌。荚膜是肺炎链球菌重要的毒力因子，生存环境信号对荚膜的调节是细菌侵袭性致病的重要方式，但这种调控机制尚不清楚。本课题组前期通过DNA-pulldown、MALDI-TOF-MS、EMSA等方法筛选出肺炎链球菌荚膜多糖的转录调节因子Mga-like，并证实其具有负调控CPS和正调控磷壁酸的作用，且它与化脓性链球菌GAS的环境信号调节转录因子Mga具有高度同源性，它也能介导葡萄糖对CPS的调节作用。本项目以Mga-like对cps的转录调控为切入点，探讨环境信号通过Mga-like介导的荚膜调控影响肺炎链球菌的侵袭性致病机制。本研究对理解细菌适应体内不同环境、导致毒力改变的机制有重要意义，并可能为肺炎链球菌性疾病的防治提供新的作用靶点。

肺炎链球菌是一种儿童临床常见的条件致病菌，也是社区获得性肺炎的首位细菌病原菌。荚膜是肺炎链球菌重要的毒力因子，生存环境信号对荚膜的调节是细菌侵袭性致病的重要方式，但这种调控机制尚不清楚。本课题组前期发现转录因子Mgaspn具有负调控荚膜多糖作用，这种作用受外界环境葡萄糖水平影响。因此，本研究拟探索MgaSpn是否通过感应细菌生存环境信号参与调控细菌荚膜多糖合成从而改变细菌毒力。本研究结果表明Mgaspn可分别与cps和lic1启动子特异性结合并负向调控小分子荚膜多糖和磷酸胆碱的含量，进而调控细菌的毒力；证实了葡萄糖水平是Mgaspn 介导调控磷酸胆碱合成的环境信号，但这种调控机制不是通过影响Mgaspn的表达水平和Mgaspn与lic1 结合能力实现，而是通过葡萄糖水平影响Mgaspn蛋白的磷酸化水平间接调控磷酸胆碱，从而影响肺炎链球菌侵袭性致病和环境适应性。本研究结果对理解细菌适应体内不同环境、导致毒力改变的机制有重要意义，对于进一步了解肺炎链球菌的侵袭性致病机制和研发新的治疗肺炎链球菌感染方案有一定的学术价值，并可能为肺炎链球菌性疾病的防治提供新的作用靶点。