Streptococcus mutans adaptation to oxidative stress by the Cid/Lrg system

 描述(申请人提供)：变形链球菌被认为是人类龋齿的主要病原体。变形链球菌能够在各种有害或应激条件下生存，并成为稳定的口腔生物膜群落的重要成员，这是其持久性和致龋性的基本要素。这些能力对于了解这种微生物如何在特定的利基环境中定居和持续至关重要，并可能与复杂的适应机制相互联系，使有机体能够在动态的口腔微生物区系中保持动态平衡。变形链球菌生理学的这一重要方面将通过研究同源的CidAB和lrgAB操纵子来实现，最近发现这两个操纵子在变形链球菌在氧气中的生长过程中高度平衡和协调，并被证明在变形链球菌的一系列关键毒力特征中发挥重要作用，包括自溶、生物膜形成、氧化和热应激以及遗传能力。更重要的是，Cid和LRG操纵子被预测为类似于噬菌体编码的Holin/antiholin蛋白(建议控制噬菌体介导的细胞死亡和裂解的活性)。该提案的目标是：1)破译CID和LRG基因之间相互调节反馈的调节回路；2)识别 研究Cid/LRG介导的变形链球菌的细胞和分子机制，以及3)评价Cid和LRG对变形链球菌体内外竞争适合度的贡献。这些目标将促进我们对变形链球菌如何在含有高度复杂的分化细胞群和动态代谢过程的生物膜中持续存在的理解，并代表着细菌程序性细胞死亡研究的新途径，将进一步加深与其他口腔链球菌和革兰氏阳性微生物相关的基础知识。此外，建立生物膜发育和细胞死亡/裂解之间的联系将为抑制龋齿的开始或进展以及改进治疗和疾病控制的可能性提供另一种有价值的见解。

 DESCRIPTION (provided by applicant): Streptococcus mutans is considered the principal etiological agent of human dental caries. The ability of the organism to survive a variety of harmful or stressful conditions and to emerge as numerically significant member of stable oral biofilm communities are essential elements for the persistence and cariogenicity of S. mutans. Such abilities are critical to understand how this organism colonizes and persists in specific niches, and are likely to interconnect with sophisticated adaptation mechanisms that allow the organism to maintain homeostasis within the dynamic oral microflora. This important aspect of S. mutans physiology will be pursued in this proposal by studying the homologous cidAB and lrgAB operons, recently identified as being highly balanced and coordinated during S. mutans growth in oxygen, as well as shown to play a significant role in a variety of key S. mutans virulence traits, including autolysis, biofilm formation, oxidative and heat stress, and genetic competence. More importantly, the cid and lrg operons were predicted to be analogous to bacteriophage-encoded holin/antiholin proteins (suggested to control the activity of bacteriophage-mediated cell death and lysis). The goals of this proposal are 1) to decipher the reciprocal regulatory circuits of regulatory feedback between the cid and lrg genes, 2) to identify and characterize the Cid/Lrg-mediated cellular and molecular mechanisms in S. mutans, and 3) to evaluate contribution of Cid and Lrg to the competitive fitness of S. mutans in-vitro and in-vivo. These objectives will advance our understanding of how S. mutans persists in biofilms that harbor a highly complex population of differentiated cells and dynamic metabolic processes, and represent a new avenue of bacterial programmed cell death research that will further fundamental knowledge relevant to other oral streptococci and Gram-positive organisms. Furthermore, establishing a link between biofilm development and cell death/lysis will provide another valuable insight into inhibition of the initiation or progression of dental caries and possibilities for improved therapy and disease control.