Pyruvate oxidase determines ecological fitness of oral streptococci

描述（由申请人提供）：血链球菌和戈登链球菌被认为是口腔生物膜的健康有益的早期定植菌。它们最初的附着影响了随后的生物膜发育和物种组成。共生血链球菌和哥氏链球菌与致龋变形链球菌的临床相关拮抗作用为制定口腔疾病预防的替代策略提供了独特的可能性。提高血链球菌和哥氏链球菌对变异链球菌等致龋物种的竞争力，可以使口腔生物膜朝着健康的方向发展。我们最近发现了丙酮酸氧化酶（SpxB）依赖性过氧化氢生产的血链球菌和哥氏链球菌是与变形链球菌种间相互作用的主要竞争因素。此外，过氧化氢诱导生物膜形成所需的细胞外DNA的释放。为了更好地理解过氧化氢在这些过程中的作用，我们建议：1)阐明H2O2产生和自相容性调控机制的差异；2)阐明SpxB依赖的H2O2产生、eDNA释放和生物膜形成之间的功能关系；3)在新的小鼠模型中探讨SpxB在宿主-细菌界面的生态学意义。这项研究提供了一种创新的方法来研究丙酮酸氧化酶依赖的过氧化氢生产的作用，利用基因组学、全局转录、蛋白质相互作用和生物统计学数据。本研究的结果将为了解环境因素和多物种环境下的生物膜生长模式如何影响口腔共生体的主要竞争因素提供更好的理解。重要的是，这些研究直接将分子分析与生物学意义联系起来。目标是利用获得的信息来提高口腔共生竞争力，例如在竞争条件下增加过氧化氢的产量。这一认识将为制定预防口腔疾病的新策略提供重要的新见解。

DESCRIPTION (provided by applicant): Streptococcus sanguinis and Streptococcus gordonii are considered health beneficial early colonizers of the oral biofilm. Their initial attachment influences subsequent biofilm development and species composition. The clinical relevant antagonism between commensals S. sanguinis and S. gordonii with cariogenic Streptococcus mutans provides the unique possibility to develop alternative strategies in oral disease prevention. Increasing S. sanguinis and S. gordonii competitiveness over cariogenic species like S. mutans could manipulate oral biofilm development towards a healthy composition. We recently identified pyruvate oxidase (SpxB) dependent hydrogen peroxide production by S. sanguinis and S. gordonii as major competitive factor in interspecies interactions with S. mutans. Furthermore, hydrogen peroxide induces the release of extracellular DNA required for biofilm formation. To better understand the role of hydrogen peroxide in these processes, we propose to: 1) elucidate the differences in the regulatory mechanisms of H2O2 production and self-compatibility by H2O2 producers, 2) elucidate the functional relationship between SpxB dependent H2O2 production, eDNA release and biofilm formation and 3) and probe ecological significance of SpxB in vivo at the host-bacterial interface in a novel murine model. This research provides an innovative approach to study the role of pyruvate oxidase dependent hydrogen peroxide production employing genomic, global transcription, protein interaction, and biostatistics data. The results of this research will provide an enhanced understanding of how environmental factors and the biofilm mode of growth in a multispecies setting influence the major competitive factor of oral commensals. Importantly, these studies directly link molecular analysis to biological significance. The goal is to use the gained information to increase oral commensal competitiveness, e.g. increasing hydrogen peroxide production under competitive conditions. This understanding should provide important new insight into the development of new strategies to prevent oral diseases.