细菌源性过氧化氢经c-di-AMP信号通路调控变异链球菌生存竞争能力的机制研究

牙菌斑生物膜内菌种间竞争在维持口腔微生态平衡中具有重要作用。变异链球菌通过SloR调控锰离子摄入、合成mutanobactin等途径抵御血链球菌等共生菌产生的过氧化氢胁迫，具体的信号途径及分子机制缺乏深入研究。c-di-AMP是调控变异链球菌生物膜形成和环境应激的关键因子。课题组前期研究发现过氧化氢作用于变异链球菌SloR影响胞内锰离子浓度，促进c-di-AMP信号介导的mutanobactin合成；c-di-AMP合成酶缺失菌株对过氧化氢敏感，在与血链球菌共培养的生物膜中竞争力降低。因此本项目假设细菌源性过氧化氢通过SloR调控c-di-AMP信号介导的mutanobactin合成，影响变异链球菌生存竞争能力。拟通过分子生物学技术，结合多菌种生物膜与动物模型验证，阐明细菌源性过氧化氢经c-di-AMP信号通路调控变异链球菌生存竞争进而影响口腔微生态的分子机制，为龋病生态防治提供新思路。

The oral microecological balance is closely associated with the development of dental caries. And the dynamic interactions between Streptococcus mutans and oral symbiotic bacteria play important roles in the regulation of oral microecological homeostasis. Streptococcus mutans inhibits the growth of oral symbiotic bacteria by synthesizing mutacins, and resists hydrogen peroxide stress produced by oral symbiotic bacteria such as Streptococcus sanguinis by regulating manganese ion uptake via SloR and synthesizing mutanobactin. However, the specific signal pathway and molecular mechanism of Streptococcus mutans in response to bacterial hydrogen peroxide stimulation were yet unclear. c-di-AMP is a key factor regulating the biofilm formation and environmental stress response of Streptococcus mutans. Our previous research found that hydrogen peroxide affected the intracellular manganese ion concentration via SloR, promoted c-di-AMP signal-mediated mutanobactin synthesis in Streptococcus mutans; c-di-AMP synthetase-deficient strain of Streptococcus mutans was sensitive to hydrogen peroxide, and its competitiveness in biofilm co-cultured with Streptococcus sanguinis was reduced. Therefore, it is assumed that bacterial hydrogen peroxide regulates c-di-AMP signal-mediated mutanobactin synthesis through SloR, affecting the survival competitiveness of Streptococcus mutans. To test this hypothesis, various molecular biological techniques, a in vitro two-species biofilm model and a rat model of dental caries will be used to elucidate the role of bacterial hydrogen peroxide in regulating the survival competitiveness of Streptococcus mutans and thus affecting oral microecology via c-di-AMP signaling pathway. Results obtained from this study will help to provide novel options and targets for the ecological prevention and treatment of dental caries.