Oxygen and Streptococcus mutans Virulence

描述（由申请方提供）：我们已经确定，变形链球菌关键毒力属性的基因表达，包括涉及生物膜形成、碳水化合物转运、酸产生、储存聚合物的催化和胞外多糖产生的基因表达，受到暴露于氧气的显著影响。此外，我们已经公开了用于响应于氧化还原而重塑细胞表面的复杂控制回路，我们已经证明其中的一些是由双组分系统和自溶素集中调节的。这项建议的目的是了解S生长的表型后果。变形链球菌在氧气存在下的作用，并剖析我们观察到变形链球菌的潜在分子基础。在空气中培养时，变形菌是一种完全不同的生物体。为了实现这些目标，我们制定了以下具体目标。目标1.厌氧或需氧培养细胞毒力相关表型特性的比较目的2.厌氧培养和需氧培养细胞表面和分泌体的比较目的3. O2响应基因的顺式和反式作用元件分析通过实施这些目标的研究计划，全面了解S.变形菌进入空气和厌氧生活将得以实现。这些研究将直接导致更好地了解这种病原体在未成熟和成熟牙菌斑中的行为。这一研究方向已经发现并将继续揭示新的途径，这些途径可能作为破坏S.变异人拟议的研究具有广泛的相关性，将有助于开发新的治疗方法，以防治龋齿和其他疾病。 公共卫生相关性：我们已经发现，人类龋齿的主要病原体，变形链球菌，经历了基因表达的重大变化，并显着重塑其表面，以响应暴露于氧气。这项研究的目标是了解这些变化如何影响这种生物体的定殖，持续和引起疾病的能力，并剖析影响这些变化的潜在调控途径。从这些研究中产生的知识将直接导致新的策略来控制龋齿，并将提供急需的洞察力，了解其他医学上重要的病原体如何改变它们的外观和行为来引起疾病。

DESCRIPTION (provided by applicant): We have established that the expression of genes for critical virulence attributes of Streptococcus mutans, including those involved in biofilm formation, carbohydrate transport, acid production, catabolism of storage polymers, and exopolysaccharide production, is dramatically affected by exposure to oxygen. Moreover, we have disclosed complex control circuits for remodeling of the cell surface in response to redox, some of which we have shown to be centrally regulated by a two- component system and autolysin. The goals of this proposal are to understand the phenotypic consequences of growth of S. mutans in the presence of oxygen and to dissect the underlying molecular basis for our observations that S. mutans is a radically different organism when cultured in air. To achieve these goals, the following Specific Aims are established. Aim 1. Comparison of virulence-related phenotypic properties of cells cultured anaerobically or aerobically Aim 2. Comparison of the surface and secretome of cells cultured anaerobically or aerobically Aim 3. Analysis of cis- and trans-acting elements of O2-responsive genes By implementing the Research Plan for these aims, a comprehensive understanding of the responses of S. mutans to air and anaerobiosis will be realized. These studies will lead directly to a better understanding of the behavior of this pathogen in immature and mature dental plaque. This line of investigation has already discovered, and will continue to disclose, novel pathways that may serve as targets to disrupt the establishment and persistence of S. mutans. The proposed studies are broadly relevant and will facilitate the development of new therapy to combat dental caries and other diseases. PUBLIC HEALTH RELEVANCE: We have discovered that the primary causative agent of human dental caries, Streptococcus mutans, undergoes major changes in gene expression and dramatically remodels its surface in response to exposure to oxygen. The goals of this research are to understand how these changes affect the ability of this organism to colonize, persist and cause disease, and to dissect the underlying regulatory pathways that effect these changes. The knowledge generated from these studies will lead directly to new strategies to control dental caries and will provide much-needed insight into how other medically-important pathogens alter their appearance and behavior to cause diseases.