唾液酸信号调控在微重力诱导后肺炎链球菌侵袭力变化中的机制研究

Streptococcus pneumoniae (S. pneumoniae) commonly conlonizes in the human nasopharynx, only causes infections when it translocates to other sites such as the middle ear, blood and lung etc. It has been reported that the virulence of S. pneumoniae increased after exposure to microgravity environment, but the underlying mechanism remained unclear.Our project members previously discovered that sialic acids (Sia), a nine-carbon sugar widely docorating on cell surface, is the key signaling molecule that affects pneumococcal colonization, transcriptional regulation of Sia operon and promotes the translocation of S. pneumoniae to the lung. Based on our research backgrounds and "Shenba" spaceflight preliminary results, we speculate that Sia could play some key roles in the pneumococcal adaptive and virulence changes under microgravity conditions.This proposal will study different pneumococci strains cultivated under various gravity condistions including simulated microgravity and real weightless in outerspace. Sia operon knock-up strain and Sia analogues will also be used as paralleled controls to investigate the effects of microgravity on the transcriptional profiles of Sia operon related genes and corresaponding proteoin expressions; the biological characters and virulence willaso be studyed using cell and mouse infection models. We aim to elucidate the molecular mechanism of how microgravity affect S. pneumoniae from the Sia point of view and the interactions between pneumococci and host cells. This study will provoide further insights for making new measures to minimize the risk of S. penumoniae infection when working in the space.

肺炎链球菌常定植人鼻咽部，在环境改变移行至中耳、血液或肺部时引起感染。研究发现：微重力环境可诱导该菌侵袭力增强。课题组成员前期报道：宿主细胞表面的唾液酸，是调控肺炎链球菌毒力因子NanA/B、唾液酸修饰/转运蛋白表达（位于同一操纵子）及促进细菌向肺转移的关键信号分子。结合预实验和神八搭载初步结果，我们提出唾液酸信号及其操纵子基因、转录调控因子MgrA可能是参与调节失重状态下肺炎链球菌侵袭力及宿主细胞炎症反应的主要机制。本项目拟使用航天搭载和模拟失重环境下培育的肺炎链球菌、唾液酸信号相关基因敲除株和抑制剂等，研究不同重力环境下唾液酸信号调控的作用和途径；并通过细胞、气道组织和BALB/c小鼠感染模型，明确微重力环境对该菌生物学和侵袭力的影响机制；在分子、组织和动物不同层面，揭示唾液酸信号途径影响微重力条件下肺炎链球菌侵袭力和与宿主反应变化的机制，为防治航天员感染提供研究基础

肺炎链球菌是人鼻咽部的常见定植菌，在环境改变移行至中耳、血液或肺部等时引起感染。近期一些研究发现微重力环境可诱导该菌生物学性状发生一定改变，这可能对航天活动中人类的健康造成威胁。本研究首次同过旋转壁式生物反应器模拟微重力环境下培养肺炎链球菌，观察不同微重力和正常重力环境培养下肺炎链球菌生长状况、碳源利用、侵袭力、毒力、基因组及转录组等方面的改变。结果发现微重力培养条件并未对肺炎链球菌的生长、毒力造成明显影响。但是肺炎链球菌对细胞的侵袭力有所下降，表现为该菌对16HBE支气管上皮细胞的粘附力的降低。另外，尽管在单一碳源的利用方面没有显著变化，但是全基因组测序发现与碳源、氨基酸、脂肪酸及DNA修复的相关的基因发生了突变。由于基因表达调控过程的复杂性，这些突变并没有造成代谢表型的改变。本研究结果为微重力环境下细菌感染特别是肺炎链球菌感染的防控提供了新的理论支持。