Oxygen and Streptococcus mutans Virulence

描述(申请人提供)：我们已经确定，变形链球菌的关键毒力属性的基因表达，包括那些参与生物膜形成、碳水化合物运输、产酸、储存聚合物的分解代谢和胞外多糖生产的基因，受到氧气暴露的显著影响。此外，我们还揭示了细胞表面重塑对氧化还原反应的复杂控制电路，其中一些我们已经证明是由一个双组分系统和自溶素集中调节的。这项建议的目标是了解变形链球菌在氧气存在下生长的表型后果，并剖析我们观察到的变形链球菌在空气中培养时是一种完全不同的有机体的潜在分子基础。为实现这些目标，确定了以下具体目标。目的1.厌氧和好氧培养细胞毒力相关表型特性的比较目的2.厌氧和好氧培养细胞表面和分泌体的比较目的3.O2反应基因顺式和反式作用元件的分析通过实施这些目标的研究计划，可以全面了解变形链球菌对空气和厌氧的反应。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。这项调查已经发现并将继续揭示新的途径，这些途径可能成为扰乱变形链球菌建立和持续存在的目标。拟议的研究具有广泛的相关性，并将有助于开发新的治疗方法来抗击龋齿和其他疾病。 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，在基因表达上经历了重大的变化，并对暴露在氧气中的表面进行了戏剧性的重塑。这项研究的目标是了解这些变化如何影响这种有机体的定植、持续和致病的能力，并剖析影响这些变化的潜在调控途径。这些研究产生的知识将直接导致控制龋齿的新策略，并将为其他医学上重要的病原体如何改变其外观和行为而导致疾病提供亟需的洞察。

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.