Cyclic di-AMP调控变异链球菌致病毒力的分子机制研究

Cyclic di-AMP（c-di-AMP）是继c-di-GMP（Cyclic di-GMP）之后新发现的细菌中的又一个重要的第二信使分子。c-di-AMP在细菌的生长以及毒力因子表达调控中起到至关重要的作用。变异链球菌是人口腔中最重要的致龋菌之一。变异链球菌细胞内c-di-AMP水平对其生物膜形成起至关重要调控作用。变异链球菌细胞内c-di-AMP水平高低直接影响变异链球菌生物膜的形成。c-di-AMP是通过其特异性结合蛋白CabPA调控变异链球菌生物膜形成的，CabPA能与VicRK双组分系统作用，调控gtfB表达，影响变异链球菌生物膜形成。c-di-AMP还可以通过影响变异链球菌的毒力而调节其在致龋微生态环境中的竞争力。因此，研究c-di-AMP调控变异链球菌致龋毒力的分子机制，并基于c-di-AMP及其相关蛋白设计的小分子药物可以为龋病防治提供新的策略。

Cyclic di-AMP (c-di-AMP) is an emerging second messenger in bacteria. It has been shown to play important roles in bacterial fitness and virulence. However, transduction of c-di-AMP signaling in bacteria and the role of c-di-AMP in biofilm formation have not been well documented. The level of c-di-AMP is modulated by activity of di-adenylyl cyclase that produces c-di-AMP and phosphodiesterase (PdeA) that degrades c-di-AMP. In this study, we determined that increased c-di-AMP levels by deletion of the pdeA gene coding for a phosphodiesterase promoted biofilm formation in Streptococcus mutans. Deletion of pdeA up-regulated expression of gtfB, the gene encoding a major glucan producing enzyme. CabPA deficiency specifically inhibited both the increased biofilm formation and the up-regulated expression of GtfB observed in the pdeA mutant. In addition, CabPA interacted with VicR, a known transcriptional factor that regulates expression of gtfB, suggesting that CabPA regulates GtfB through VicR. Decreased intracellular c-di-AMP levels in the SmDAC deficiency resulted in an attenuation of cariogenicity on a rat caries study. Therefore，screening of small molecule inhibitors of SmDAC provides a new strategy for prevention dental caries.